Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and their use

ABSTRACT

The invention relates to compounds of general formula (I), a method for the production thereof and the use thereof as pharmacologically effective substances for a broad medical indication spectrum. Furthermore, selective adenosine receptor ligands, preferably selective adenosine A1-, adenosine A2a- and/or adenosine A2b-receptor ligands are provided for the prophylaxis and/or the treatment of diseases, especially cardiovascular diseases, diseases of the urogenital region, diseases of the respiratory tract, inflammatory and neuroinflammatory diseases, diabetes, especially pancreatic diabetes, neurodegenerative diseases, pain states, cancer as well as liver fibrosis and liver cirrhosis.

The present invention relates to substituted2-thio-3,5-dicyano-4-aryl-6-amino-pyridines, to a process for theirpreparation and to their use as active compounds for medicaments.

The present invention furthermore provides the use ofadenosine-receptor-selective ligands for the prophylaxis and/ortreatment of various disorders.

Adenosine, a nucleoside consisting of adenine and D-ribose, is anendogenous factor having cell-protective activity, in particular undercell-damaging conditions with limited oxygen and substrate supply, suchas, for example, in the case of ischemia in various organs (for exampleheart and brain).

Adenosine is formed intracellularly as an intermediate during thedegradation of adenosine 5′-monophosphate (AMP) andS-adenosylhomocysteine, but it can be released from the cell, in whichcase it acts as a hormone-like substance or neurotransmitter by bindingto specific receptors.

Under normoxic conditions, the concentration of free adenosine in theextracellular space is very low. However, under ischemic or hypoxicconditions, the extracellular concentration of adenosine in the affectedorgans is increased dramatically. Thus, it is known, for example, thatadenosine inhibits platelet degradation and increases the blood supplyto the coronary vessels of the heart. Furthermore, it acts on the heartrate, on the release of neurotransmitters and on lymphocytedifferentiation.

The aim of these actions of adenosine is to increase the oxygen supplyof the affected organs and/or to reduce the metabolism of these organsin order to adjust the metabolism of the organ to the blood supply ofthe organ under ischemic or hypoxic conditions.

The action of adenosine is mediated via specific receptors. To date,subtypes A1, A2a, A2b and A3 are known. The actions of these adenosinereceptors are mediated intracellularly by the messenger cAMP. In thecase of the binding of adenosine to the A2a or A2b receptors, theintracellular cAMP is increased via activation of the membrane-bondadenylate cyclase, whereas binding of adenosine to A1 or A3 receptorsresults in a decrease of the intracellular cAMP concentration viainhibition of adenylate cyclase.

According to the invention, “Adenosine-receptor-selective ligands” aresubstances which bind selectively to one or more subtypes of theadenosine receptors, thus either mimicking the action of adenosine(adenosine agonists) or blocking its action (adenosine antagonists).

According to their receptor selectivity, adenosine-receptor-selectiveligands can be divided into different categories, for example ligandswhich bind selectively to the A1 or A2 receptors of adenosine and in thecase of the latter also, for example, those which bind selectively tothe A2a or the A2b receptors of adenosine. Also possible are adenosinereceptor ligands which bind selectively to a plurality of subtypes ofthe adenosine receptors, for example ligands which bind selectively tothe A1 and the A2, but not to the A3 receptors of adenosine.

The abovementioned receptor selectivity can be determined by the effectof the substances on cell lines which, after stable transfection withthe corresponding cDNA, express the receptor subtypes in question (seethe publication M. E. Olah, H. Ren, J. Ostrowski, K. A. Jacobson, G. L.Stiles, “Cloning, expression, and characterization of the unique bovineA1 adenosine receptor. Studies on the ligand binding site bysite-directed mutagenesis.” in J. Biol. Chem. 267 (1992) pages10764-10770, the disclosure of which is hereby fully incorporated by wayof reference).

The effect of the substances on such cell lines can be monitored bybiochemical measurement of the intracellular messenger cAMP (see thepublication K. N. Klotz, J. Hessling, J. Hegler, C. Owman, B. Kull, B.B. Fredholm, M. J. Lohse, “Comparative pharmacology of human adenosinereceptor subtypes—characterization of stably transfected receptors inCHO cells” in Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998) pages1-9, the disclosure of which is hereby fully incorporated by way ofreference).

The “adenosine-receptor-specific” ligands known from the prior art aremainly derivatives based on natural adenosine (S.-A. Poulsen and R. J.Quinn, “Adenosine receptors: new opportunities for future drugs” inBioorganic and Medicinal Chemistry 6 (1998) pages 619-641). However,most of the adenosine ligands known from the prior art have thedisadvantage that their action is not really receptor-specific, thattheir activity is less than that of natural adenosine or that they haveonly very weak activity after oral administration. Thus, because of thedisadvantages mentioned above, they are mainly only used forexperimental purposes.

It is now an object of the following invention to find or providecompounds which have a wide therapeutic range and can serve as activecompounds for the prophylaxis and/or treatment of various diseases.

In particular, it is an object of the present invention to find orprovide substances which preferably act as adenosine-receptor-selectiveligands and are suitable for the prophylaxis and/or treatment of variousdisorders, in particular disorders of the cardiovascular system(cardiovascular disorders) or inflammatory disorders, but additionallyalso disorders of the urogenital system, the respiratory tract, thecentral nervous system, the diabetes (in particular diabetes mellitus)and cancer.

It is a further object of the present invention to find or provideadenosine-receptor-selective ligands having a high specificity of actionfor the abovementioned purposes.

Accordingly, the present invention relates to compounds of the generalformula (I)

in which:

-   R¹, R², R³ are identical or different and independently of one    another are selected from the group of the following substituents:    -   hydrogen;    -   hydroxyl;    -   optionally substituted (C₁-C₈)-alkyl;    -   optionally substituted (C₆-C₁₀)-aryl;    -   optionally substituted (C₁-C₈)-alkoxy;    -   —O—(CH₂)_(n)—CH═CH₂ where n=0, 1 or 2;    -   halogen;    -   nitro;    -   cyano;    -   —C(O)—R⁵;    -   —C(O)—NR⁶R⁷;    -   —NR⁶R⁷;    -   —NR⁶—C(O)—R⁸;    -   —O—C(O)—R⁸;    -   —SO₂—NR⁶R⁷; and    -   —NR⁶—SO₂R⁸,    -   where:    -   R⁵ denotes:        -   hydrogen;        -   hydroxyl;        -   optionally substituted (C₁-C₈)-alkyl;        -   optionally substituted (C₃-C₇)-cycloalkyl;        -   optionally substituted (C₁-C₈)-alkoxy;        -   optionally substituted (C₆-C₁₀)-aryl;        -   optionally substituted (C₆-C₁₀)-aryloxy; or        -   —O—(CH₂)_(n)—[(C₆-C₁₀)-aryl] where n=1, 2 or 3,        -   where the (C₆-C₁₀)-aryl group may be fused via two adjacent            ring atoms to optionally substituted (C₄-C₇)-cycloalkyl,    -   or    -   R⁵ represents a 5- to 7-membered saturated or unsaturated        heterocycle which for its part may be mono- or polysubstituted        by        -   an oxo group (═O);        -   halogen;        -   optionally substituted (C₁-C₈)-alkyl;        -   nitro;        -   cyano;        -   hydroxyl;        -   optionally substituted (C₆-C₁₀)-aryl; or        -   by (C₁-C₈)-alkoxy,    -   or    -   R⁵ represents optionally substituted 5- to 6-membered heteroaryl        having up to 3 heteroatoms from the group consisting of N, O and        S, where the heterocycle and the heteroaryl ring may each        optionally be fused via two adjacent ring atoms to optionally        substituted (C₆-C₁₀)-aryl or optionally substituted        (C₄-C₇)-cycloalkyl,    -   and    -   R⁶ and R⁷ are identical or different and represent        -   hydrogen;        -   optionally substituted (C₁-C₈)-alkyl;        -   optionally substituted (C₆-C₁₀)-aryl; or        -   represent optionally substituted 5- to 6-membered heteroaryl            having        -   up to 3 heteroatoms from the group consisting of N, O and S    -   or    -   R⁶ and R⁷ together with the nitrogen atom to which they are        optionally attached form a 5- to 7-membered saturated or        unsaturated heterocycle having up to 3 heteroatoms from the        group consisting of N, O and S which for its part may optionally        be mono- or polysubstituted by identical or different        substituents from the group consisting of        -   an oxo group (═O);        -   halogen;        -   (C₁-C₈)-alkyl;        -   nitro;        -   cyano;        -   hydroxyl;        -   (C₆-C₁₀)-aryl; or        -   (C₁-C₈)-alkoxy,    -   and    -   R⁸ represents hydroxyl;        -   NR⁶R⁷ where R⁶ and R⁷ are as defined above;        -   optionally substituted (C₁-C₈)-alkyl;        -   (C₁-C₈)-alkoxy;        -   optionally substituted (C₆-C₁₀)-aryl;        -   (C₆-C₁₀)-aryloxy; or        -   —O—(CH₂)_(n)—[(C₆-C₁₀)-aryl] where n=1, 2 or 3,            and-   R⁴ represents straight-chain or branched (C₁-C₈)-alkyl or    (C₂-C₈)-alkenyl which are optionally mono- or polysubstituted by    -   hydroxyl;    -   halogen;    -   cyano;    -   —C(O)—R⁵ where R⁵ is as defined above;    -   —C(O)—NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above;    -   —SO₂—NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are as defined above;    -   —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is as defined        above;

(C₁-C₈)-alkoxy;

-   -   optionally substituted (C₆-C₁₀)-aryloxy;    -   optionally substituted 5- to 6-membered heteroaryl having up to        3 heteroatoms from the group consisting of N, O and S;    -   optionally substituted (C₆-C₁₀)-aryl; or    -   by a 5- to 7-membered saturated or unsaturated heterocycle        having up to 3 heteroatoms from the group consisting of N, O and        S which for its part may optionally be mono- or polysubstituted        by identical or different substituents from the group consisting        of an oxo group (═O); halogen; (C₁-C₈)-alkyl; nitro; cyano;        hydroxyl; (C₆-C₁₀)-aryl; or by (C₁-C₈)-alkoxy,    -   where the heterocycle and the heteroaryl ring may each        optionally be fused via two adjacent ring atoms to optionally        substituted (C₆-C₁₀)-aryl,        or

-   R⁴ represents a 5- to 7-membered saturated or unsaturated    heterocycle having up to 3 heteroatoms from the group consisting of    N, O and S, which for its part may optionally be mono- or    polysubstituted by identical or different substituents from the    group consisting of an oxo group (═O); halogen; (C₁-C₈)-alkyl;    nitro; cyano; hydroxyl; (C₆-C₁₀)-aryl; or by (C₁-C₈)-alkoxy, and    which may optionally be fused via two adjacent ring atoms to    optionally substituted (C₆-C₁₀)-aryl or optionally substituted    (C₄-C₇)-cycloalkyl,    and their tautomers and their respective salts, hydrates and    alkoxides,    except for the following compounds of the general formula (I), in    which the radicals R¹, R², R³ and R⁴ are as defined below:    -   R¹=R²=H; R³=para-OH; R⁴=—CH₂-Z where Z=CN, C(O)—OC₂H₅,        4-Br—C₆H₄—CO, 4-n-butyl-C₆H₄—CO, H, C₆H₅, C(O)—O—CH₂—C₆H₅,        C(O)—OCH₃, C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl,        4-Cl—C₆H₄—CO, 3-Br—C₆H₄—CO, 4-C₆H₅—C₆H₄—CO, 4—CH₃—C₆H₄—CO,        3,4-Cl₂—C₆H₃—CO;    -   R¹=R²=H; R³=meta-OH; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—NH—CO,        2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO;    -   R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=4-CH₃—C₆H₄—CO, H,        2-oxo-benzopyranyl-3-carbonyl, (CH₂)₃—CH₃, 4-C₆H₅—C₆H₄;    -   R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃, CN, 2-naphthyl;    -   R¹=R²=H; R³=para-butoxy; R⁴=—CH₂-Z where Z=4-Cl—C₆H₅, C(O)—OCH₃,        C(O)—C₆H₅, CH═CH₂, C(O)—NH₂, H, 4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO,        C(O)—OC₂H₅, C(O)—O—CH₂—C₆H₅, 2-oxo-benzopyranyl-3-carbonyl,        C(O)—NH—C₆H₅, CN;    -   R¹=R²=H; R³=para-bromo; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO,        4-Cl—C₆H₄—CO, C(O)—NH₂, C(O)—OCH₃, 4-Cl—C₆H₅, 4-Br—C₆H₄—NH—CO;    -   R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO,        C(O)—NH₂, C(O)—O—CH₂—C₆H₅, CN;    -   R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z where Z=2-naphthyl, CH₃;    -   R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Z where Z=2-naphthyl, CH₃;    -   R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.

Some of the abovementioned substances which can be used in accordancewith the present invention for the prophylaxis and/or treatment ofdisorders are novel, and some are also known from the literature (seeDyachenko et al., Russian Journal of Chemistry, Vol. 33, No. 7, 1997,pages 1014-1017 and Vol. 34, No. 4, 1998, pages 557-563; Dyachenko etal., Chemistry of Heterocyclic Compounds, Vol. 34, 1998, pages 188-194;Elnagdi et al., Zeitschrift für Naturforschung, Vol. 47b, 1992, pages572-578; Riguera et al., Eur. J. Med. Chem. 33, 1998, pages 887-897; J.Vaquero, Thesis, University of Alcala de Henares, Madrid, Spain, 1981).However, in the literature, a therapeutic use of the known compounds hashitherto not been described. The first time this has happened is in thecontext of the present invention.

Accordingly, the present invention also provides the use of theabovementioned compounds of the general formula (I), including thecompounds excluded above, for the prophylaxis and/or treatment ofdisorders.

Depending on the substitution pattern, the compounds of the formula (I)can exist in stereoisomeric forms which are either like image and mirrorimage (enantiomers) or not like image and mirror image (diastereomers).The invention relates both to the enantiomers or diastereomers and totheir respective mixtures. The racemic forms, like the diastereomers,can be separated in a known manner into the stereoisomerically uniformcomponents. Likewise, the present invention also relates to the othertautomers of the compounds of the formula (I) and their salts.

Physiologically acceptable salts of the compounds of the formula (I) canbe salts of the substances according to the invention with mineralacids, carboxylic acids or sulfonic acids. Particular preference isgiven, for example, to salts with hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonicacid, trifluoroacetic acid, acetic acid, propionic acid, lactic acid,tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts which may be mentioned include salts with customary bases, suchas, for example, alkali metal salts (for example sodium or potassiumsalts), alkaline earth metal salts (for example calcium or magnesiumsalts) or ammonium salts, derived from ammonia or organic amines suchas, for example, diethylamine, triethylamine, ethyldiisopropylamine,procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine,1-ephenamine or methylpiperidine.

Definitions in the Context of the Present Invention:

-   -   Halogen generally represents fluorine, chlorine, bromine or        iodine. Preference is given to fluorine, chlorine or bromine.        Very particular preference is given to fluorine or chlorine.    -   In the context of the present invention, (C₁-C₈)-alkyl,        (C₁-C₆)-alkyl and (C₁-C₄)-alkyl represent a straight-chain or        branched alkyl radical having 1 to 8; 1 to 6 and 1 to 4 carbon        atoms, respectively. Examples which may be mentioned are:        methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,        tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl and        n-octyl. Preference is given to a straight-chain or branched        alkyl radical having 1 to 6 carbon atoms. Particular preference        is given to a straight-chain or branched alkyl radical having 1        to 4 carbon atoms.    -   Optionally substituted (C₁-C₈)-alkyl, (C₁-C₆)-alkyl and        (C₁-C₄)-alkyl, as used in the present invention, denotes an        above-defined straight-chain or branched alkyl radical having 1        to 8; 1 to 6 and 1 to 4 carbon atoms, respectively, which for        its part can be mono- or polysubstituted by identical or        different substituents. Substituents which may be mentioned are        in particular the following substituents: halogen (fluorine,        chlorine, bromine, iodine); cyano; nitro; carboxyl; hydroxyl;        straight-chain or branched (C₁-C₈)-alkoxy, preferably        (C₁-C₆)-alkoxy, in particular (C₁-C₄)-alkoxy, where the alkoxy        radical for its part may optionally be substituted;        straight-chain or branched (C₂-C₈)-alkenyl, preferably        (C₂-C₆)-alkenyl, in particular (C₂-C₄)-alkenyl, where the        alkenyl radical for its part may optionally be substituted;        (C₆-C₁₀)-aryl, in particular phenyl or naphthyl, where the        (C₆-C₁₀)-aryl radical for its part may optionally be        substituted; (C₁-C₄)-alkylsulfonyloxy, where the        (C₁-C₄)-alkylsulfonyloxy radical for its part may optionally be        substituted; phenylsulfonyl or p-tolylsulfonyl; straight-chain        or branched (C₁-C₈)-thioalkyl, where the thioalkyl radical for        its part may optionally be substituted; straight-chain or        branched mono-, di- and/or trihalogeno-(C₁-C₈)-alkyl, in        particular trifluoromethyl; straight-chain or branched mono-,        di- and/or trihalogeno-(C₁-C₈)-alkoxy, in particular        trifluoromethoxy; acyl; amino, N—[(C₁-C₈)-alkyl]-amino and/or        N-di-[(C₁-C₈)-alkyl]-amino, where the alkyl radical for its part        may optionally be substituted; and (C₁-C₈)-alkoxycarbonyl, where        the alkoxycarbonyl radical for its part may optionally be        substituted.    -   In the context of the present invention, (C₆-C₁₀)-aryl        represents an aromatic radical having 6 to 10 carbon atoms.        Preferred aryl radicals are phenyl and naphthyl.    -   In the context of the present invention, the term optionally        substituted (C₆-C₁₀)-aryl represents an aromatic radical as        defined above having 6 to 10 carbon atoms which for its part may        be mono- or polysubstituted by identical or different        substituents, in particular by: halogen (fluorine, chlorine,        bromine, iodine); cyano; nitro; carboxyl; hydroxyl;        straight-chain or branched (C₁-C₈)-alkyl, preferably        (C₁-C₆)-alkyl, in particular (C₁-C₄)-alkyl, where the alkyl        radical for its part may optionally be substituted;        straight-chain or branched (C₁-C₈)-alkoxy, preferably        (C₁-C₆)-alkoxy, in particular (C₁-C₄)-alkoxy, where the alkoxy        radical for its part may optionally be substituted;        straight-chain or branched (C₂-C₈)-alkenyl, preferably        (C₂-C₆)-alkenyl, in particular (C₂-C₄)-alkenyl, where the        alkenyl radical for its part may optionally be substituted;        straight-chain or branched (C₁-C₈)-thioalkyl, where the        thioalkyl radical for its part may optionally be substituted;        straight-chain or branched mono-, di- and/or        trihalogeno-(C₁-C₈)-alkyl, in particular trifluoromethyl;        straight-chain or branched mono-, di- and/or        trihalogeno-(C₁-C₈)-alkoxy, in particular trifluoromethoxy;        acyl; amino, N—[(C₁-C₈)-alkyl]-amino and/or        N-di-[(C₁-C₈)-alkyl]-amino, where the alkyl radical for its part        may optionally be substituted; N—[(C₁-C₆)-alkoxy]-aldimino;        (C₁-C₈)-alkoxycarbonyl, where the alkoxycarbonyl radical for its        part may optionally be substituted; and (C₆-C₁₀)-aryl, in        particular phenyl or naphthyl, where the (C₆-C₁₀)-aryl radical        for its part may optionally be substituted.    -   (C₆-C₁₀)-Aryloxy represents a group —O—(C₆-C₁₀)-aryl, in        particular a group —O-phenyl or —O-naphthyl, where otherwise        reference may be made to the above definition of (C₆-C₁₀)-aryl.    -   Optionally substituted (C₆-C₁₀)-aryloxy denotes a group        —O—(C₆-C₁₀)-aryl as defined above where, with respect to the        substituents of the (C₆-C₁₀)-aryl group, reference may be made        to the above definition under optionally substituted        (C₆-C₁₀)-aryl.    -   (C₁-C₈)-Alkoxy, (C₁-C₆)-alkoxy and (C₁-C₄)-alkoxy, as used in        the present invention and also in the definitions of        (C₁-C₈)-alkoxycarbonyl represents a straight-chain or branched        alkoxy radical having 1 to 8; 1 to 6 and 1 to 4 carbon atoms,        respectively. Examples which may be mentioned are: methoxy,        ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy,        n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, n-heptoxy and        n-octoxy. Preference is given to a straight-chain or branched        alkoxy radical having 1 to 6 carbon atoms. Particular preference        is given to a straight-chain or branched alkoxy radical having 1        to 4 carbon atoms.    -   In the context of the present invention, optionally substituted        (C₁-C₈)-alkoxy, (C₁-C₆)-alkoxy and (C₁-C₄)-alkoxy denotes a        straight-chain or branched alkoxy radical as defined above        having 1 to 8, 1 to 6 and 1 to 4 carbon atoms, respectively,        which may optionally be mono- or polysubstituted by identical or        different substituents, in particular by the following        substituents: halogen (fluorine, chlorine, bromine, iodine);        cyano; nitro; carboxyl; hydroxyl; straight-chain or branched        (C₂-C₈)-alkenyl, preferably (C₂-C₆)-alkenyl, in particular        (C₂-C₄)-alkenyl, where the alkenyl radical for its part may        optionally be substituted; straight-chain or branched        (C₁-C₈)-thioalkyl, where the thioalkyl radical for its part may        optionally be substituted; straight-chain or branched mono-, di-        and/or trihalogeno-(C₁-C₈)-alkyl, in particular trifluoromethyl;        straight-chain or branched mono-, di- and/or        trihalogeno-(C₁-C₈)-alkoxy, in particular trifluoromethoxy;        acyl; amino, N—[(C₁-C₈)-alkyl]-amino and/or        N-di-[(C₁-C₈)-alkyl]-amino, where the alkyl radical for its part        may optionally be substituted; or (C₁-C₈)-alkoxycarbonyl, where        the alkoxycarbonyl radical for its part may optionally be        substituted.    -   In the context of the invention, (C₃-C₇)-Cycloalkyl generally        represents a carbon ring having 3 to 7 carbon atoms, such as,        for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or        cycloheptyl.    -   In the context of the invention, optionally substituted        (C₃-C₇)-cycloalkyl generally represents a (C₃-C₇)-cycloalkyl        radical as defined above which may optionally be mono- or        polysubstituted by identical or different substituents, in        particular by a (C₁-C₈)-alkyl radical, preferably a        (C₁-C₆)-alkyl radical, very particularly preferably a        (C₁-C₄)-alkyl radical, which for its part may in turn be mono-        or polysubstituted as defined above.    -   In the context of the invention, a 5- to 6-membered aromatic        heterocycle having up to 3 heteroatoms from the group consisting        of S, N and O generally represents a monocyclic heteroaromatic        radical which is attached via a ring carbon atom of the        heteroaromatic radical and, if appropriate, also via a ring        nitrogen atom of the heteroaromatic radical. Examples which may        be mentioned are: furanyl (for example furan-2-yl, furan-3-yl),        pyrrolyl (for example pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl),        thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl,        pyrimidyl, pyridazinyl. Preference is given to pyridyl,        pyrimidyl, pyridazinyl, furanyl, imidazolyl and thiazolyl.    -   In the context of the invention, an optionally substituted 5- to        6-membered aromatic heterocycle having up to 3 heteroatoms from        the group consisting of S, N and O generally represents a        heterocycle as defined above which may be mono- or        polysubstituted by identical or different substituents from the        group consisting of nitro; amino; guanidino; aminocarbonyl;        halogen, preferably chlorine or fluorine; (C₁-C₆)-alkyl,        preferably (C₁-C₄)-alkyl, as defined above, which for its part        may optionally be substituted; or by (C₆-C₁₀)-aryl as defined        above which for its part may optionally be substituted.

Compounds which are preferred in the context of the invention arecompounds of the general formula (I),

in which:

-   R¹, R², R³ are identical or different and independently of one    another are selected from the group of the following substituents:    -   hydrogen;    -   hydroxyl;    -   optionally substituted (C₁-C₆)-alkyl;    -   optionally substituted phenyl or naphthyl;    -   optionally substituted (C₁-C₆)-alkoxy;    -   —O—(CH₂)_(n)—CH═CH₂ where n=1 or 2;    -   fluorine, chlorine, bromine;    -   nitro;    -   cyano;    -   —C(O)—R⁵;    -   —C(O)—NR⁶R⁷;    -   —NR⁶R⁷;    -   —NR⁶—C(O)—R⁸;    -   —O—C(O)—R⁸;    -   —SO₂—NR⁶R⁷; and    -   —NR⁶—SO₂R⁸,    -   where:    -   R⁵ denotes:        -   hydrogen;        -   hydroxyl;        -   optionally substituted (C₁-C₆)-alkyl;        -   optionally substituted (C₃-C₇)-cycloalkyl;        -   optionally substituted (C₁-C₆)-alkoxy;        -   optionally substituted phenyl or naphthyl;        -   optionally substituted phenyloxy or naphthyloxy; or        -   —O—(CH₂)_(n)-phenyl where n=1, 2 or 3,        -   where the phenyl or naphthyl group may be fused via two            adjacent ring atoms to optionally substituted            (C₄-C₇)-cycloalkyl,    -   or    -   R⁵ represents a 5- to 7-membered saturated or unsaturated        heterocycle which for its part may be mono- or polysubstituted        by        -   an oxo group (═O);        -   fluorine, chlorine, bromine;        -   optionally substituted (C₁-C₆)-alkyl;        -   nitro;        -   cyano;        -   hydroxyl;        -   optionally substituted phenyl or naphthyl; or        -   by (C₁-C₆)-alkoxy,    -   or    -   R⁵ represents optionally substituted 5- to 6-membered heteroaryl        having up to 3 heteroatoms from the group consisting of N, O and        S,        -   where the heterocycle and the heteroaryl ring may each            optionally be fused via two adjacent ring atoms to            optionally substituted phenyl or naphthyl or optionally            substituted (C₄-C₇)-cycloalkyl,    -   and    -   R⁶ and R⁷ are identical or different and represent        -   hydrogen;        -   optionally substituted (C₁-C₆)-alkyl;        -   optionally substituted phenyl or naphthyl; or        -   represent optionally substituted 5- to 6-membered heteroaryl            having up to 3 heteroatoms from the group consisting of N, O            and S    -   or    -   R⁶ and R⁷ together with the nitrogen atom to which they are        optionally attached form a 5- to 7-membered saturated or        unsaturated heterocycle having up to 3 heteroatoms from the        group consisting of N, O and S which for its part may optionally        be mono- or polysubstituted by identical or different        substituents from the group consisting of        -   an oxo group (═O);        -   fluorine, chlorine, bromine;        -   (C₁-C₆)-alkyl;        -   nitro;        -   cyano;        -   hydroxyl;        -   phenyl or naphthyl; or        -   (C₁-C₆)-alkoxy,    -   and    -   R⁸ represents NR⁶R⁷ where R⁶ and R⁷ are as defined above;        -   optionally substituted (C₁-C₆)-alkyl;        -   (C₁-C₆)-alkoxy;        -   optionally substituted phenyl or naphthyl;        -   phenyloxy or naphthyloxy; or        -   —O—(CH₂)_(n)-phenyl where n=1, 2 or 3,            and-   R⁴ represents straight-chain or branched (C₁-C₆)-alkyl or    (C₂-C₆)-alkenyl which are optionally mono- or polysubstituted by    -   hydroxyl;    -   fluoro, chloro, bromine;    -   cyano;    -   —C(O)—R⁵ where R⁵ is as defined above;    -   —C(O)—NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above;    -   —SO₂—NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are as defined above;    -   —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is as defined        above;    -   (C₁-C₆)-alkoxy;    -   optionally substituted phenyloxy or naphthyloxy;    -   optionally substituted 5- to 6-membered heteroaryl having up to        3 heteroatoms from the group consisting of N, O and S;    -   optionally substituted phenyl or naphthyl; or    -   by a 5- to 7-membered saturated or unsaturated heterocycle        having up to 3 heteroatoms from the group consisting of N, O and        S, which for its part may optionally be mono- or polysubstituted        by identical or different substituents from the group consisting        of an oxo group (═O); fluorine, chlorine, bromine;        (C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl or naphthyl; or by        (C₁-C₆)-alkoxy,    -   where the heterocycle and the heteroaryl ring may each        optionally be fused via two adjacent ring atoms to optionally        substituted phenyl or naphthyl,-   or-   R⁴ represents a 5- to 7-membered saturated or unsaturated    heterocycle having up to 3 heteroatoms from the group consisting of    N, O and S,    -   which for its part may optionally be mono- or polysubstituted by        identical or different substituents from the group consisting of        an oxo group (═O); fluorine, chlorine, bromine; (C₁-C₆)-alkyl;        nitro; cyano; hydroxyl; phenyl or naphthyl; or by (C₁-C₆)-alkoxy        and    -   which may optionally be fused via two adjacent ring atoms to        optionally substituted phenyl or naphthyl or optionally        substituted (C₄-C₇)-cycloalkyl,        and their tautomers and their respective salts, hydrates and        alkoxides,        except for the following compounds of the general formula (I),        in which the radicals R¹, R², R³ and R⁴ are as defined below:    -   R¹=R²=H; R³=para-OH; R⁴=—CH₂-Z where Z=CN, C(O)—OC₂H₅,        4-Br—C₆H₄—CO, 4-n-butyl-C₆H₄—CO, H, C₆H₅, C(O)—O—CH₂—C₆H₅,        C(O)—OCH₃, C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl,        4-Cl—C₆H₄—CO, 3-Br—C₆H₄—CO, 4-C₆H₅—C₆H₄—CO, 4-CH₃—C₆H₄—CO,        3,4-Cl₂—C₆H₃—CO;    -   R¹=R²=H; R³=meta-OH; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—NH—CO,        2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO;    -   R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=4—CH₃—C₆H₄—CO, H,        2-oxo-benzopyranyl-3-carbonyl, (CH₂)₃—CH₃, 4—C₆H₅—C₆H₄;    -   R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃, CN, 2-naphthyl;    -   R¹=R²=H; R³=para-butoxy; R⁴=—CH₂-Z where Z=4-Cl—C₆H₅, C(O)—OCH₃,        C(O)—C₆H₅, CH═CH₂, C(O)—NH₂, H, 4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO,        C(O)—OC₂H₅, C(O)—O—CH₂—C₆H₅, 2-oxo-benzopyranyl-3-carbonyl,        C(O)—NH—C₆H₅, CN;    -   R¹=R²=H; R³=para-bromo; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO,        4-Cl—C₆H₄—CO, C(O)—NH₂, C(O)—OCH₃, 4-Cl—C₆H₅, 4-Br—C₆H₄—NH—CO;    -   R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO,        C(O)—NH₂, C(O)—O—CH₂—C₆H₅, CN;    -   R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z where Z=2-naphthyl, CH₃;    -   R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.

Particularly preferred compounds are the compounds of the generalformula (I)

in which:

-   R¹, R², R³ are identical or different and independently of one    another are selected from the group of the following substituents:    -   hydrogen;    -   hydroxyl;    -   optionally substituted (C₁-C₄)-alkyl;    -   optionally substituted phenyl;    -   optionally substituted (C₁-C₄)-alkoxy;    -   —O—(CH₂)_(n)—CH═CH₂ where n=1;    -   fluorine, chlorine;    -   nitro;    -   cyano;    -   —C(O)—R⁵;    -   —C(O)—NR⁶R⁷;    -   —NR⁶R⁷;    -   —NR⁶—C(O)—R⁸;    -   —O—C(O)—R⁸;    -   —SO₂—NR⁶R⁷; and    -   —NR⁶—SO₂R⁸,    -   where:    -   R⁵ denotes:        -   hydrogen;        -   hydroxyl;        -   optionally substituted (C₁-C₄)-alkyl;        -   optionally substituted (C₃-C₇)-cycloalkyl;        -   optionally substituted (C₁-C₄)-alkoxy;        -   optionally substituted phenyl;        -   optionally substituted phenyloxy; or        -   —O—(CH₂)_(n)-phenyl where n=1,        -   where the phenyl group may be fused via two adjacent ring            atoms to optionally substituted (C₅-C₆)-cycloalkyl,    -   or    -   R⁵ represents a 5- to 7-membered saturated or unsaturated        heterocycle which for its part may be mono- or polysubstituted        by        -   an oxo group (═O);        -   fluorine, chlorine;        -   optionally substituted (C₁-C₄)-alkyl;        -   nitro;        -   cyano;        -   hydroxyl;        -   optionally substituted phenyl; or        -   by (C₁-C₄)-alkoxy,    -   or    -   R⁵ represents optionally substituted 5- to 6-membered heteroaryl        having up to 3 heteroatoms from the group consisting of N, O and        S, selected from the group consisting of furanyl, pyrrolyl,        thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl,        pyrimidyl and pyridazinyl,        -   where the heterocycle and the heteroaryl ring may each            optionally be fused via two adjacent ring atoms to            optionally substituted phenyl or optionally substituted            (C₅-C₆)-cycloalkyl,    -   and    -   R⁶ and R⁷ are identical or different and represent        -   hydrogen;        -   optionally substituted (C₁-C₄)-alkyl;        -   optionally substituted phenyl; or        -   represent optionally substituted 5- to 6-membered heteroaryl            having up to 3 heteroatoms from the group consisting of N, O            and S selected from the group consisting of furanyl,            pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,            triazolyl, pyridyl, pyrimidyl and pyridazinyl,    -   or    -   R⁶ and R⁷ together with the nitrogen atom to which they are        optionally attached form a 5- to 7-membered saturated or        unsaturated heterocycle having up to 3 heteroatoms from the        group consisting of N, O and S which for its part may optionally        be mono- or polysubstituted by identical or different        substituents from the group consisting of        -   an oxo group (═O);        -   fluorine, chlorine;        -   (C₁-C₄)-alkyl;        -   nitro;        -   cyano;        -   hydroxyl;        -   phenyl; or        -   (C₁-C₄)-alkoxy,    -   and    -   R⁸ represents NR⁶R⁷ where R⁶ and R⁷ are as defined above;        -   optionally substituted (C₁-C₄)-alkyl;        -   (C₁-C₄)-alkoxy;        -   optionally substituted phenyl;        -   phenyloxy; or        -   —O—(CH₂)_(n)-phenyl where n=1,            and-   R⁴ represents straight-chain or branched (C₁-C₄)-alkyl or    (C₂-C₄)-alkenyl which are optionally mono- or polysubstituted by    -   hydroxyl;    -   fluorine, chlorine;    -   cyano;    -   —C(O)—R⁵ where R⁵ is as defined above;    -   —C(O)—NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶C(O)—R⁸ where R⁶ and R⁸ are as defined above;    -   —SO₂—NR⁶R⁷ where R⁶ and R⁷ are as defined above;    -   —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are as defined above;    -   —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is as defined        above;    -   (C₁-C₄)-alkoxy;    -   optionally substituted phenyloxy;    -   optionally substituted 5- to 6-membered heteroaryl having up to        3 heteroatoms from the group consisting of N, O and S selected        from the group consisting of furanyl, pyrrolyl, thienyl,        thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl        and pyridazinyl;    -   optionally substituted phenyl; or    -   by a 5- to 7-membered saturated or unsaturated heterocycle        having up to 3 heteroatoms from the group consisting of N, O and        S which for its part may optionally be mono- or polysubstituted        by identical or different substituents from the group consisting        of an oxo group (═O); fluorine, chlorine; (C₁-C₄)-alkyl; nitro;        cyano; hydroxyl; phenyl; or by (C₁-C₄)-alkoxy,    -   where the heterocycle and the heteroaryl ring may each        optionally be fused via two adjacent rings atoms to optionally        substituted phenyl,        or-   R⁴ represents a 5- to 7-membered saturated or unsaturated    heterocycle having up to 3 heteroatoms from the group consisting of    N, O and S,    -   which for its part may optionally be mono- or polysubstituted by        identical or different substituents from the group consisting of        an oxo group (═O); fluorine, chlorine; (C₁-C₄)-alkyl; nitro;        cyano; hydroxyl; phenyl; or by (C₁-C₄)-alkoxy and    -   which may optionally be fused via two adjacent ring atoms to        optionally substituted phenyl or optionally substituted        (C₅-C₆)-cycloalkyl,        and their tautomers and their respective salts, hydrates and        alkoxides,        except for the following compounds of the general formula (I),        in which the radicals R¹, R², R³ and R⁴ are as defined below:    -   R¹=R²=H; R³=para-OH; R⁴=—CH₂-Z where Z=CN, C(O)—OC₂H₅,        4-Br—C₆H₄—CO, 4-n-butyl-C₆H₄—CO, H, C₆H₅, C(O)—O—CH₂—C₆H₅,        C(O)—OCH₃, C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl,        4-Cl—C₆H₄—CO, 3-Br—C₆H₄—CO, 4-C₆H₅—C₆H₄—CO, 4—CH₃—C₆H₄—CO,        3,4-Cl₂—C₆H₃—CO;    -   R¹=R²=H; R³=meta-OH; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—NH—CO,        2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO;    -   R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=4-CH₃—C₆H₄—CO, H,        2-oxo-benzopyranyl-3-carbonyl, 4-C₆H₅—C₆H₄;    -   R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃, CN;

R¹=R²=H; R³=para-butoxy; R⁴=—CH₂-Z where Z=4-Cl—C₆H₅, C(O)—OCH₃,C(O)—C₆H₅, CH═CH₂, C(O)—NH₂, H, 4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO, C(O)—OC₂H₅,C(O)—O—CH₂—C₆H₅, 2-oxo-benzopyranyl-3-carbonyl, C(O)—NH—C₆H₅, CN;

-   -   R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO,        C(O)—NH₂, C(O)—O—CH₂—C₆H₅, CN;    -   R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=para-OCH₃; R⁴—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.

Particular preference according to the invention is given to compoundsof the general formula (I)

in which:

-   R¹, R², R³ are identical or different and independently of one    another are selected from the group of the following substituents:    -   hydrogen;    -   hydroxyl;    -   methyl;    -   trifluoromethyl;    -   methoxy;    -   radicals of the formulae —O—CH₂—CH₂—OH, —O—CH₂—COOH or        —O—CH₂—CH═CH₂;    -   fluorine, chlorine or bromine;    -   nitro;    -   cyano;    -   —C(O)OH or —C(O)OCH₃;    -   —C(O)NH₂;    -   —NH₂;    -   —NH—C(O)—CH₃;    -   —O—C(O)—CH₃ or —O—C(O)—C₂H₅;    -   radicals of the formulae    -   and    -   —NH—SO₂CH₃ or —NH—SO₂C₆H₅,        and-   R⁴ represents straight-chain or branched (C₁-C₄)-alkyl which is    optionally mono- or polysubstituted by    -   hydroxyl;    -   amino;    -   —C(O)—OCH₃;    -   —C(O)—NH₂, —C(O)—HNCH₃, —C(O)—HNC₂H₅, or —C(O)—HNC₆H₅;    -   —NHC(O)NH₂, —NHC(O)NHCH₃, —NHC(O)NHC₂H₅, —NHC(O)OCH₃ or    -   —NHC(O)OC₂H₅;    -   —SO₂—NH₂;    -   —NH—SO₂—CH₃ or —NH—SO₂—C₂H₅;    -   —OCH₃;    -   phenyl, which may be substituted by nitro, cyano, fluorine,        methoxy, difluoromethoxy, methoxycarbonyl or        p-tolylsulfonylmethyl;    -   pyridyl, furyl, imidazolyl, benzimidazolyl or thiazolyl, which        may in each case be mono- or disubstituted by identical or        different substituents from the group consisting of methyl,        nitro and chlorine;    -   oxadiazolyl which may be substituted by phenyl or methoxyphenyl;    -   or    -   a radical of the formula        or-   R⁴ represents allyl or 3,3-dimethylallyl,-   and their tautomers and their respective salts, hydrates and    alkoxides,    except for the following compounds of the general formula (I), in    which the radicals R¹, R², R³ and R⁴ are as defined below:    -   R¹=R²=H; R³=para-OH; R⁴=—CH₂-Z where Z=H, C₆H₅, C(O)—OCH₃;    -   R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=H;    -   R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z where Z=C(O)—NH₂;    -   R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=para-OCH₃; R⁴—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.

Very particular preference according to the invention is given tocompounds of the general formula (I)

in which:

-   R¹, R², R³ are identical or different and independently of one    another are selected from the group of the following substituents:    -   hydrogen;    -   hydroxyl;    -   methyl;    -   methoxy;    -   radicals of the formulae —O—CH₂—CH₂—OH, —O—CH₂—COOH or        —O—CH₂—CH═CH₂;    -   fluorine or chlorine;    -   nitro;    -   cyano;    -   —C(O)OH or —C(O)OCH₃;    -   —C(O)NH₂;    -   NH₂;    -   —NH—C(O)CH₃;    -   —O—C(O)—CH₃ or —O—C(O)—C₂H₅;    -   radicals of the formulae    -   and    -   —NH—SO₂CH₃ or —NH—SO₂C₆H₅,        and-   R⁴ represents straight-chain or branched (C₁-C₄)-alkyl which is    optionally mono- or polysubstituted by    -   hydroxyl;    -   amino;    -   —C(O)—OCH₃;    -   —C(O)—NH₂, —C(O)—HNCH₃, —C(O)—HNC₂H₅, or —C(O)—HNC₆H₅;    -   —NHC(O)NH₂, —NHC(O)NHCH₃, —NHC(O)NHC₂H₅, —NHC(O)OCH₃ or    -   —NHC(O)OC₂H₅;    -   —SO₂—NH₂;    -   —NH—SO₂—CH₃ or —NH—SO₂—C₂H₅;    -   —OCH₃;    -   phenyl;    -   ortho-nitrophenyl; or    -   a radical of the formula        or-   R⁴ represents allyl,    and their tautomers and their respective salts, hydrates and    alkoxides,    except for the following compounds of the general formula (I), in    which the radicals R¹, R², R³ and R⁴ are as defined below:    -   R¹=R²=H; R³=para-OH; R⁴=—CH₂-Z where Z=H, C₆H₅, C(O)—OCH₃;    -   R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=H;    -   R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z where Z=C(O)—NH₂;    -   R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Z where Z=CH₃;    -   R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.

The present invention also provides a process for preparing thecompounds of the general formula (I).

According to a first variant of the process according to the invention,the compounds of the general formula (I) are prepared byreacting compounds of the general formula (II)

in which the radicals R¹, R² and R³ are as defined abovewith compounds of the general formula (III)R⁴—X  (III),in which R⁴ is as defined aboveandX represents a nucleofugic group (preferably halogen, in particularchlorine, bromine or iodine, or mesylate, tosylate, triflate or1-imidazolyl),in inert solvents, if appropriate in the presence of a base.

The process described above can be illustrated in an exemplary manner bythe equation below:

If the radical R⁴ in the general formula (I) has the meaning of

alkyl, substituted by the radicals —NR⁶—C(O)—R⁸, —NR⁶—C(O)—NR⁶R⁷,—NR⁶—SO₂—R⁸,

where the radicals R⁶, R⁷ and R⁸ are as defined above,

it is alternatively, according to a second variant of the processaccording to the invention, also possible to prepare the compounds ofthe general formula (I) by initially reacting the compounds of thegeneral formula (II) with 2-bromoethylamine to give compounds of thegeneral formula (IV)

which are then reacted with compounds of the general formulaR⁹—Y  (V),in which

-   R⁹ has the meaning —C(O)—R⁸, —C(O)—O—R⁸, —C(O)—NR⁶R⁷, —SO₂—R⁸ where    R⁸ is as defined above    -   and-   Y represents a nucleofugic group, preferably halogen, in particular    chlorine, bromine or iodine, or mesylate, tosylate, triflate or    1-imidazolyl,    or else-   R⁹ has the meaning R⁶    -   and-   Y represents the group O═C═N—,    in inert solvents, if appropriate in the presence of a base.

The second variant, described above, of the process according to theinvention can be illustrated in an exemplary manner by the followingequation:

The nucleofugic group X, which is sometimes also referred to as leavinggroup, can be introduced into the reaction separately or else begenerated in situ by customary methods, for example by the “Mitsunobureaction”.

Suitable solvents for the process according to the invention are allorganic solvents which are inert under the reaction conditions. Theseinclude alcohols such as methanol, ethanol and isopropanol, ketones suchas acetone and methyl ethyl ketone, acyclic and cyclic ethers such asdiethyl ether and tetrahydrofuran, esters such as ethyl acetate or butylacetate, hydrocarbons such as benzene, xylene, toluene, hexane orcyclohexane, dimethylformamide, acetonitrile, pyridine, dimethylsulfoxide (DMSO), chlorinated hydrocarbons such as dichloromethane,chlorobenzene or dichloroethane or hexamethylphosphoric triamide. Wateris also suitable for use as solvent. Particular preference is given todimethylformamide. It is also possible to use mixtures of the solventsmentioned above.

Suitable bases are the customary inorganic or organic bases. Thesepreferably include alkali metal hydroxides, such as, for example, sodiumhydroxide or potassium hydroxide, or alkali metal carbonates, such assodium carbonate or potassium carbonate or sodium bicarbonate orpotassium bicarbonate, or sodium methoxide or potassium methoxide orsodium ethoxide or potassium ethoxide or potassium tert-butoxide, orelse amides, such as sodium amide, lithium bis-(trimethylsilyl)amide orlithium diisopropylamide, or organometallic compounds, such asbutyllithium or phenyllithium, or else amines, such as triethylamine andpyridine. Preference is given to the alkali metal carbonates and alkalimetal bicarbonates.

Here, the base can be employed in an amount of from 1 to 10 mol,preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1mol of the compounds of the general formula (II) or (IV).

The reaction generally takes place in a temperature range of from −78°C. to reflux temperature. preferably in the range from −78° C. to +40°C., in particular at room temperature.

The reaction can be carried out at atmospheric, elevated or reducedpressure (for example in the range from 0.5 to 5 bar). In general, thereaction is carried out at atmospheric pressure.

The person skilled in the art is familiar with numerous modifications ofthe conditions mentioned above which are within the knowledge of theaverage expert and within the scope of the present invention.

The compounds of the general formulae (II) are likewise known per se tothe person skilled in the art or can be prepared by customary methodsknown from the literature. Reference may be made in particular to thefollowing publications, the respective content of which is expresslyincorporated herein by way of reference:

-   Dyachenko et al., Russian Journal of Chemistry, Vol. 33, No. 7,    1997, pages 1014-1017 and Vol. 34, No. 4, 1998, pages 557-563;-   Dyachenko et al., Chemistry of Heterocyclic Compounds, Vol. 34, No.    2, 1998, pages 188-194;-   Qintela et al., European Journal of Medicinal Chemistry, Vol. 33,    1998, pages 887-897;-   Kandeel et al., Zeitschrift für Naturforschung 42b, 107-111 (1987).

It is also possible to prepare the compounds of the general formula (II)from compounds of the general formula (VI) by reaction with an alkalimetal sulfide. This preparation method can be illustrated in anexemplary manner by the equation below:

The alkali metal sulfide used is preferably sodium sulfide in an amountof from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to4 mol, based on 1 mol of the compounds of the general formula (VI).

Suitable solvents are all organic solvents which are inert under thereaction conditions. These include N,N-dimethylformamide,N-methylpyrrolidinone, hexamethylphosphoric triamide, pyridine andacetonitrile. Particularly preference is given to N,N-dimethylformamide.It is also possible to use mixtures of the solvents mentioned above.

The reaction is generally carried out in a temperature range of from+20° C. to reflux temperature, preferably in the range from +20° C. to+120° C., in particular at from +60° C. to +100° C.

The reaction can be carried out at atmospheric, elevated or reducedpressure (for example in the range from 0.5 to 5 bar). In general, thereaction is carried out at atmospheric pressure.

The person skilled in the art is familiar with numerous modifications ofthe conditions mentioned above which are within the knowledge of theaverage expert and within the scope of the present invention.

The compounds of the general formulae (VI) are likewise known per se tothe person skilled in the art or can be prepared by customary methodsknown from the literature. Reference may be made in particular to thepublication Kambe et al., Synthesis, 531 (1981) the content of which isexpressly incorporated herein by way of reference.

The compounds of the general formulae (III) or (V) are eithercommercially available or known per se to the person skilled in the artor can be prepared by customary methods.

Surprisingly, the compounds of the general formula (I) have anunforeseeable useful pharmacological activity spectrum and are thereforesuitable in particular for the prophylaxis and/or treatment ofdisorders.

This is because it has now been found, unexpectedly, that the substancesof the formula (I) above are suitable for the prophylaxis and/ortreatment of a large number of disorders, i.e. in particular, forexample, disorders of the cardiovascular system (cardiovasculardisorders); urogenital disorders; respiratory disorders; inflammatoryand neuroinflammatory disorders; diabetes, in particular diabetesmellitus; cancer; and finally also neurodegenerative disorders, such as,for example, Parkinson's disease, and also pain.

In the context of the present invention, cardiovascular disorders are tobe understood as meaning, in particular, for example the followingdisorders: coronary heart disease; hypertension (high blood pressure);restinosis such as, for example, restinosis after balloon dilatation ofperipheral blood vessels; arteriosclerosis; tachycardia; arrhythmias;peripheral and cardiovascular disorders; stable and unstable anginapectoris; and atrial fibrillation.

The compounds of the general formula (I) are furthermore also suitablefor reducing the myocardial area effected by an infarct.

The compounds of the general formula (I) are furthermore suitable forthe treatment and prophylaxis of thromboembolic disorders and ischemiassuch as myocardial infarction, stroke and transitory ischemic attacks.

A further area of indication for which the compounds of the generalformula (I) are suitable is the prophylaxis and/or therapy of urogenitaldisorders, such as, for example, irritable bladder, erectile dysfunctionand female sexual dysfunction, and additionally also the prophylaxisand/or treatment of inflammatory disorders, such as, for example, asthmaand inflammable dermatoses, of neuroinflammatory disorders of thecentral nervous system, such as, for example, conditions after cerebralinfarction, Alzheimer's disease, furthermore also neurodegenerativedisorders such as Parkinson's disease, and also pain.

A further area of indication is respiratory disorders such as, forexample, asthma, chronic bronchitis, pulmonary emphysema,bronchiectases, cystic fibrosis (mucoviscidosis) and pulmonaryhypertension.

The compounds of the general formula (I) are furthermore also suitablefor the prophylaxis and/or therapy of hepatic fibrosis and cirrhosis ofthe liver.

Finally, the compounds of the general formula (I) are also suitable forthe prophylaxis and/or therapy of diabetes, in particular diabetesmellitus.

Accordingly, the present invention also relates to the use of thesubstances of the general formula (I) for preparing medicaments andpharmaceutical compositions for the prophylaxis and/or treatment of theclinical features mentioned above.

The present invention furthermore relates to a method for theprophylaxis and/or the treatment of the clinical pictures mentionedabove using substances of the general formula (I).

The pharmaceutical activity of the abovementioned compounds of thegeneral formula (I) can be explained by their action as selectiveligands on individual subtypes or a plurality of subtypes of theadenosine receptors, in particular as selective ligands on adenosine A1,adenosine A2a and/or adenosine A2b receptors, preferably as selectiveligands on adenosine A1 and/or adenosine A2b receptors.

In the context of the present invention, “selective” are adenosinereceptor ligands where, firstly, a clear effect on one or more adenosinereceptor subtypes and, secondly, no or a considerably weaker effect onone or more other adenosine receptor subtypes can be observed, where,with respect to the test methods for the selectivity of action,reference is made to the test methods described in section A. II.

Compared to adenosine receptor ligands of the prior art, the substancesof the general formula (I) are much more selective. Thus, for example,compounds of the general formula (I) in which R⁴ represents(C₁-C₄)-alkyl which is substituted by a group of the formula —C(O)NR⁶R⁷,where R⁶ and R⁷ are identical or different and are hydrogen oroptionally substituted (C₁-C₃)-alkyl, are generally selective onadenosine A2b receptors.

On the other hand, compounds of the general formula (I) in which R⁴represents (C₁-C₄)-alkyl substituted by one or more hydroxyl groupsgenerally act selectively on adenosine A1 receptors.

Compounds of the general formula (I) in which R⁴ represents(C₁-C₄)-alkyl substituted by imidazolyl or optionally substitutedbenzyl, in turn, generally act selectively on adenosine A1 and adenosineA2b receptors.

This receptor selectivity can be determined by biochemical measurementof the intracellular messenger cAMP in cells which specifically onlyexpress one subtype of the adenosine receptors. In the case of agonists,an increase in the intracellular cAMP concentration is observed; in thecase of antagonists, a decrease in the intracellular cAMP concentrationafter prior stimulation with adenosine or adenosine-like substances isobserved (see the publications B. Kull, G. Arslan, C. Nilsson, C. Owman,A. Lorenzen, U. Schwabe, B. B. Fredholm, “Differences in the order ofpotency for agonists but not antagonists at human and rat adenosine A2Areceptors”, Biochem. Pharmacol., 57 (1999) pages 65-75; and S. P.Alexander, J. Cooper, J. Shine, S. J. Hill, “Characterization of thehuman brain putative A2B adenosine receptor expressed in Chinese hamsterovary (CHO.A2B4) cells”, Br. J. Pharmacol., 119 (1996) pages 1286-90,the respective disclosure of which is hereby expressly incorporated byway of reference).

Accordingly, the present invention also provides the use of selectiveadenosine receptor ligands, in particular of selective adenosine A1,adenosine A2a and/or adenosine A2b receptor ligands, for preparingmedicaments and pharmaceutical compositions for the prophylaxis and/ortreatment of disorders, in particular, for example, disorders of thecardiovascular system (cardiovascular disorders); urogenital disorders;inflammatory and neuroinflammatory disorders; neurodegenerativedisorders; respiratory disorders; hepatic fibrosis, cirrhosis of theliver; cancer; and finally diabetes, in particular diabetes mellitus,where, with respect to the individual areas of indication, reference isalso made to what has been said above.

Thus, compounds of the general formula (I) which bind selectively toadenosine A1 receptors are preferably suitable for myocardial protectionand for the prophylaxis and/or treatment of tachycardias, atrialarrhythmias, cardiac insufficiency, of acute kidney failure, diabetesand of pain. Compounds of the general formula (I) which bind selectivelyto adenosine A2a receptors, on the other hand, are preferably suitablefor the prophylaxis and/or treatment of thromboembolic disorders, ofneurodengenerative disorders such as Parkinson's disease and also forwound healing. Compounds of the general formula (I) which bindselectively to adenosine A2b receptors, in turn, are preferably suitablefor the prophylaxis and/or therapy of hepatic fibrosis, of myocardialinfarction, of neuroinflammatory disorders, Alzheimer's disease, ofurogenital incontinence and also of respiratory disorders such as, forexample, asthma and chronic bronchitis.

The present invention also provides medicaments and pharmaceuticalcompositions comprising at least one selective adenosine and/oradenosine A2b receptor ligand, preferably at least one compound of thegeneral formula (I), together with one or more pharmacologicallyacceptable excipients or carriers, and their use for the purposesmentioned above.

Suitable for administering the compounds of the general formula (I) areall customary administration forms, i.e. oral, parenteral, inhalative,nasal, sublingual, rectal or external, such as, for example,transdermal, with particular preference oral or parenteral. In the caseof parenteral administration, particular mention may be made ofintravenous, intramuscular and subcutaneous administration, for exampleas a subcutaneous depot. Very particular preference is given to oraladministration.

Here, the active compounds can be administered on their own or in theform of preparations. Suitable preparations for oral administration areinter alia tablets, capsules, pellets, sugar-coated tablets, pills,granules, solid and liquid aerosols, syrups, emulsions, suspensions andsolutions. Here, the active compound has to be present in such aquantity that a therapeutic effect is obtained. In general, the activecompound can be present in a concentration of from 0.1 to 100% byweight, in particular from 0.5 to 90% by weight, preferably from 5 to80% by weight. In particular, the concentration of the active compoundshould be 0.5-90% by weight, i.e. the active compound should be presentin quantitites sufficient to achieve the dosage range mentioned.

To this end, the active compounds can be converted in a manner known perse into the customary preparations. This is achieved using inertnontoxic pharmaceutically suitable carriers, excipients, solvents,vehicles, emulsifiers and/or dispersants.

Excipients which may be mentioned are, for example: water, nontoxicorganic solvents such as, for example, paraffins, vegetable oils (forexample sesame oil), alcohols (for example ethanol, glycerol), glycols(for example polyethylene glycol), solid carriers, such as natural orsynthetic ground minerals (for example talc or silicates), sugars (forexample lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and glidants (for example magnesium sulfate).

In the case of oral administration, tablets may, of course, also containadditives such as sodium citrate, together with adjuvants such asstarch, gelatin and the like. Aqueous preparations for oraladministration may furthermore be admixed with flavor enhancers orcolorants.

In general, it has been found to be advantageous to administer, in thecase of parenteral administration, quantities of from about 0.1 to about10 000 μg/kg, preferably from about 1 to about 1 000 μg/kg, inparticular from about 1 μg/kg to about 100 μg/kg, of bodyweight, toobtain effective results. In the case of oral administration, thequantity is from about 0.1 to about 10 mg/kg, preferably from about 0.5to about 5 mg/kg, in particular from about 1 to about 4 mg/kg, ofbodyweight.

In spite of this, it may still be required, depending on bodyweight,administration route, individual response to the active compound, thetype of preparation and the time or interval at which administrationtakes place, to deviate from the quantities mentioned.

The present invention is illustrated by the examples below; however,these examples are only intended to facilitate a better understanding ofthe invention and not to restrict the invention in any way.

A. EVALUATION OF THE PHYSIOLOGICAL ACTIVITY

I. Demonstration of the Cardiovascular Action

Langendorff Heart of the Rat:

After opening the thoracic cage of anesthetized rats, the heart isremoved quickly and introduced into a conventional Langendorffapparatus. The coronary arteries are perfused at a constant volume (10ml/min), and the resulting perfusion pressure is recorded via anappropriate pressure sensor. In this arrangement, a decrease of theperfusion pressure corresponds to a relaxation of the coronary arteries.At the same time, the pressure which is developed by the heart duringeach contraction is measured via a balloon introduced into the leftventricle and a further pressure sensor. The frequency of the isolatedbeating heart is calculated from the number of contractions per timeunit.

In this test arrangement, the following values were obtained for thecoronary perfusion pressure (the stated percentage refers to thereduction of the coronary perfusion pressure in percent at therespective concentration): Compound of the formula (I) used

 Reduction of the coronary perfusion pressure in percent     at aconcentration of 10⁻⁷ g/ml      10⁻⁶ g/ml R¹ = R² = H no effect observedabout 26% R³ = para-CH₃ R⁴ = —CH₂—CH(OH)(CH₂OH) (compound of example A198) R¹ = R² = H no effect observed about 37% R³ = para-CH₃ R⁴ =—CH₂-phenyl (compound of example A 189) R¹ = R² = H about 42% about 68%R³ = meta-OH R⁴ = —CH₂—CH₂OH (compound of example A 43) R¹ = R² = Habout 40% about 75% R³ = para-OH R⁴ = —CH₂—CH₂OH (compound of example21) R¹ = R² = H about 64% about 63% R³ = para-OH R⁴ = 2-imidazolylmethyl(compound of example A 379)

At the stated concentrations, the substances tested had no effect on thepressure developed during the contraction in the left ventricle and noeffect on the heart rate. Thus, it was demonstrated that the substancesact selectively only on coronary perfusion.

II. Demonstration of the Receptor Selectivity (Adenosine A1, A2a. A2band A3 Receptor Selectivity)

Cells of the permanent line CHO (Chinese Hamster Ovary) were stablytransfected with cDNA for the adenosine receptor subtypes A1, A2a, A2band A3. Binding of the substances to the A2a or A2b receptor subtypeswas determined by measuring the intracellular cAMP concentration inthese cells using a conventional radioimmunological assay (cAMP-RIA, IBLGmbH, Hamburg, Germany).

In the case of the action of the substances as agonists, binding of thesubstances is expressed in an increase of the intracellular cAMPconcentration. In these experiments, the adenosine analogue NECA(5-N-ethylcarboxamido-adenosine), which binds unselectively, but withhigh affinity, to all adenosine receptor subtypes and has agonisticaction (Klotz, K. N., Hessling, J., Hegler, J., Owman, C., Kull, B.,Fredholm, B. B., Lohse, M. J., Comparative pharmacology of humanadenosine receptor subtypes—characterization of stably transfectedreceptors in CHO cells, Naunyn Schmiedebergs Arch Pharmacol, 357 (1998),1-9) was used as reference compound.

The adenosine receptors A1 and A3 are coupled to a Gi protein, i.e.stimulation of these receptors results in an inhibition of adenylatecyclase and thus a reduction of the intracellular cAMP level. Toidentify A1/A3 receptor agonists, the adenylate cyclase is stimulatedusing forskolin. However, additional stimulation of the A1/A3 receptorsinhibits adenylate cyclase, so that it is possible to detect A1/A3receptor agonists by a comparatively low concentration of cAMP in thecell.

To demonstrate an antagonistic effect on adenosine receptors, therecombinant cells transfected with the corresponding receptor wereprestimulated with NECA, and the effect of the substances on a reductionof the intracellular cAMP concentration by this prestimulation wasexamined. In these experiments, XAC (xanthine amine congener), whichbinds unselectively, but with high affinity, to all adenosine receptorsubtypes and has antagonistic action (Müller, C. E., Stein, B.,Adenosine receptor antagonists: structures and potential therapeuticapplications, Current Pharmaceutical Design, 2 (1996), 501-530) was usedas reference compound.

In the experiments below, the intracellular cAMP concentration in CHOcells which had been transfected with cDNA for the A2b receptor wasdetermined. What is stated is the cAMP concentration in percent in allcells in a well of a microtiter plate, based on the control valueobtained without any substances acting on the cells: Compound of theformula (I) used

Concentration of intracellular cAMP in percent at a     concentration of10⁻⁹ M 10⁻⁸ M 10⁻⁷ M 10⁻⁶ M 10⁻⁵ M NECA (reference) 363 340 858 12261263 R¹ = R² = H 837 947 900 R³ = para-OH R⁴ = —CH₂—C(O)NH₂ (compound ofexample A 1) R¹ = R² = H 253 432 384 R³ = para-OH R⁴ = —CH₂—CH₂OH(compound of example 21) R¹ = R² = H 347 674 784 R³ = meta-OH R⁴ =—CH₂—CH₂OH (compound of example A 43) R¹ = R² = H 463 716 753 R³ =meta-OH R⁴ = —CH₂—CH(CH3)OH (compound of example A 46) R¹ = R² = H 100178 438 586 571 R³ = H R⁴ = —CH₂—CH₂OH (compound of example A 104) R¹ =R² = H 870 846 861 936 1140 R³ = para-OH R⁴ = 2-imidazolylmethyl(compound of example A 379)

In these experiments, it was possible to block the action of allsubstances by the antagonist XAC, which is unselective, but highlyspecific for adenosine receptors.

In the experiments below, the intracellular cAMP concentration in CHOcells which had been transfected with cDNA for the A2a receptor wasdetermined. What is stated is the cAMP concentration in percent in allcells in a well of a microtiter plate, based on the control valueobtained without any substances acting on the cells: Compound of theformula (I) Concentration of intracellular cAMP in percent at a usedconcentration of

10⁻⁹ M 10⁻⁸ M 10⁻⁷ M 10⁻⁶ M 10⁻⁵ M NECA (reference) 585 800 1301 19922075 R¹ = R² = H 92 117 208 R³ = para-OH R⁴ = —CH₂—C(O)NH₂ (compound ofexample A 1) R¹ = R² = H 143 117 R³ = para-OH R⁴ = —CH₂—CH₂OH (compoundof example 21) R¹ = R² = H 117 200 317 R³ = meta-OH R⁴ = —CH₂—CH₂OH(compound of example A 43) R¹ = R² = H 67 108 183 R³ = meta-OH R⁴ =—CH₂—CH(CH3)OH (compound of example A 46) R¹ = R² = H 104 107 107 146212 R³ = H R⁴ = —CH₂—CH₂OH (compound of example A 104) R¹ = R² = H 93160 218 235 291 R³ = para-OH R⁴ = 2-imidazolylmethyl (compound ofexample A 379)

In these experiments, it was possible to block the action of allsubstances by the antagonist XAC, which is unselective, but highlyspecific for adenosine receptors.

In the following experiments, the intracellular cAMP concentration inCHO cells transfected with the cDNA for the A1 receptor was determined.What is stated is the cAMP concentration in percent in all cells of awell of a microtiter plate, based on the control value obtained withoutthe action of any substance but after prestimulation with 1 μM offorskolin for 15 min (in these measurements, the cAMP concentrationwithout prestimulation with forskolin is 18%): Concentration ofintracellular cAMP in percent at a concentration of Compound of theformula (I) used

10⁻⁷ M 10⁻⁶ M 10⁻⁵ M NECA (reference) 24 24 28 R¹ = R² = H 18 24 22 R³ =meta-OH R⁴ = —CH₂—CH₂OH (compound of example A 43) R¹ = R² = H 28 23 21R³ = H R⁴ = —CH₂—CH₂OH (compound of example A 104) R¹ = R² = H 34 34 35R³ = para-OH R⁴ = 2-imidazolylmethyl (compound of example A 379)

Thus, the compound of example A 1 has a clear agonistic effect on cellswhich express the adenosine receptor A2b and virtually no effect oncells with the A2a receptor. In contrast, the compounds from example A43 and A 104 have a clear agonistic effect on cells with the A 1receptor, virtually no effect on cells with A2a receptors and aconsiderably weaker effect on cells with the A2b receptor and aretherefore selective adenosine A1 receptor agonists. The compound ofexample A 379, on the other hand, has a clear agonistic effect on cellswith the A2b receptor, virtually no effect on cells with A2a receptorsand a comparably weaker effect on cells with the A1 receptor and is thusa selective adenosine A2b receptor agonist.

B. SYNTHESIS EXAMPLES Example 12-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}-N-methyl-acetamide

At room temperature (RT), 53.6 mg (0.2 mmol) of2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and45.6 mg (0.3 mmol) of N-methylbromo-acetamide are stirred in 0.5 ml ofdimethylformamide (DMF) together with 33.6 mg (0.4 mmol) of NaHCO₃ for 4hours. Thin-layer chromatography (TLC) (CH₂Cl₂/CH₃OH 10:1) showscomplete conversion. The entire mixture is diluted with water and ethylacetate (EA) and the EA phase is dried with MgSO₄ and concentrated underreduced pressure. The residue crystallizes from methanol.

Yield: 45 mg (66.3% of theory), white crystals

Mass spectrum: molecular mass calculated: 339, found [M+H]⁺=340.3

Example 22-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}-N,N-diethylacetamide

At RT, 53.6 mg (0.2 mmol) of2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and58.2 mg (0.3 mmol) of N,N-diethylbromoacetamide are stirred in 0.5 ml ofDMF together with 33.6 mg (0.4 mmol) of NaHCO₃ for 4 hours. TLC(CH₂Cl₂/CH₃OH 10:1) shows complete conversion. The entire mixture isdiluted with water and ethyl acetate and the EA phase is dried withMgSO₄ and concentrated under reduced pressure. The residue crystallizesfrom methanol.

Yield: 50 mg (65.5% of theory), white crystals

Mass spectrum: molecular mass calculated: 381, found [M+H]⁺=382

Example 32-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}-N-ethylacetamide

At RT 0.76 g (2 mmol) of2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and0.5 g (3 mmol) of N-ethylbromoacetamide are stirred in 5 ml of DMFtogether with 0.34 g (4 mmol) of NaHCO₃ for 4 hours. After dilution withwater, the mixture is extracted with ethyl acetate and the ethyl acetatephase is dried with MgSO₄ and concentrated under reduced pressure. Thesolid residue obtained after concentration is stirred with methanol. Thecrystals are filtered off with suction and dried under reduced pressure.

Yield: 0.49 g (69.5% of theory), crystals

Mass spectrum: molecular mass calculated: 353, found [M+H]⁺=354.2

Example 42-Amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile

268 mg (1 mmol) of2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile, 105mg (1 mmol) of 2-bromoethylamine hydrobromide and 168 mg (2 mmol) ofNaHCO₃ are stirred in 1 ml of DMF for 1 hour. The entire mixture isdiluted with a few milliliters of 1N HCl. The crystals are filtered offwith suction and dried under reduced pressure.

Yield: 200 mg (64.2% of theory), yellow crystals

Mass spectrum: molecular mass calculated: 311, found [M+H]⁺=312

Example 5N-(2-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}ethyl)-acetamide

At RT 60 mg (0.2 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileand 30 mg (0.3 mmol) of N-acetylimidazole are stirred in 0.5 ml of DMFfor 1 hour. Water is slowly added dropwise, the mixture becomes slightlyturbid and the crude product crystallizes out. The product is filteredoff with suction, washed with water and dried under reduced pressure.This gives 53 mg of yellow crystals. The crystals are dissolved in 1 mlof a 1:1 mixture of CH₂Cl₂/CH₃OH, and a few drops of concentratedammonia are added (removal of diacetylated byproduct). The mixture isstirred at RT for 5 hours. The product crystallizes out when thereaction solution is concentrated. The product is filtered off withsuction and washed with methanol.

Yield: 37 mg (52.3% of theory), almost white crystals

Mass spectrum: molecular mass calculated: 353, found [M+H]⁺=354

Example 62-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}methylcarbamate

Under argon, 31.1 mg (0.1 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended at RT in 1 to 2 ml of dichloromethane, and the mixture iscooled to from −20 to −25° C. At this temperature, 30.3 mg (0.3 mmol) oftriethylamine and 28,3 mg (0.3 mmol) of methyl chloroformate are added.The mixture is stirred at −20 C for 30 minutes and then allowed to warmto 0° C. over a period of 1 hour. The mixture is concentrated underreduced pressure, 4 ml of a 2 molar NH₃ solution in methanol are addedand the mixture is stirred at RT for 1 hour. The mixture is thenconcentrated, dissolved in 600 μl of DMSO and purified by preparativeHPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 600 μl of DMSO solution

Yield: 21.7 mg (58.7% of theory) of product

Mass spectrum: molecular mass calculated: 369, found [M+H]⁺=370.1

Example 72-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}ethylcarbamate

Under argon, 31.1 mg (0.1 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended at RT in 1 to 2 ml of dichloromethane, and the mixture iscooled to from −20 to −25° C. At this temperature, 30.3 mg (0.3 mmol) oftriethylamine and 32.6 mg (0.3 mmol) of ethyl chloroformate are added.The mixture is stirred at −20° C. for 30 minutes and then allowed towarm to 0° C. over a period of 1 hour. The mixture is concentrated underreduced pressure, 4 ml of a 2 molar NH₃ solution in methanol are addedand the mixture is stirred at RT for 1 hour. The mixture is thenconcentrated, dissolved in 600 μl of DMSO and purified by preparativeHPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 600 μl of DMSO solution

Yield: 20.5 mg (53.5% of theory) of product

Mass spectrum: molecular mass calculated: 383, found [M+H]⁺=384.2

Example 84-[2-Amino-3,5-dicyano-6-({2-[(methoxycarbonyl)amino]ethyl}sulfanyl)-4-pyridinyl]phenyl-methylcarbonate

Under argon, 31.1 mg (0.1 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended at RT in 1 to 2 ml of dichloromethane, and the mixture iscooled to from −20 to −25° C. At this temperature, 10.1 mg (0.1 mmol) oftriethylamine and 9.4 mg (0.1 mmol) of methyl chloroformate are added.The mixture is stirred at −20° C. for 30 minutes and then allowed towarm to 0° C. over a period of 1 hour. The mixture is then concentrateddissolved in 600 μl of DMSO and purified by preparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 600 μl of DMSO solution

Yield: 11.2 mg (26.2% of theory) of product

Mass spectrum: molecular mass calculated: 427, found [M+H]⁺=428.2

Example 94-[2-Amino-3,5-dicyano-6-({2-[(methoxycarbonyl)amino]ethyl}sulfanyl)-4-pyridinyl]phenyl-ethylcarbonate

Under argon 31.1 mg (0.1 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended at RT in 1 to 2 ml of dichloromethane, and the mixture iscooled to from −20 to −25° C. At this temperature, 10.1 mg (0.1 mmol) oftriethylamine and 10.9 mg (0.1 mmol) of ethyl chloroformate are added.The mixture is stirred at −20° C. for 30 minutes and then allowed towarm to 0° C. over a period of 1 hour. The mixture is then concentrated,dissolved in 600 μl of DMSO and purified by preparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 600 μl of DMSO solution

Yield: 15.2 mg (33.4% of theory) of product

Mass spectrum: molecular mass calculated: 455, found [M+H]⁺=456.2

Example 10N-(2-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}-ethyl)urea

31.1 mg (0.1 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended in 0.91 ml of 1N HCl, and 8.1 mg (0.1 mmol) of potassiumcyanate are added. After the addition of a few drops of methanol, themixture is stirred at 50° C. for a total of 10 hours. The crystals arefiltered off with suction and washed with water and ether.

Yield: 16 mg (45.1% of theory) of product

Mass spectrum: molecular mass calculated: 354, found [M+H]⁺=355.1

Example 11N-(2-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}ethyl)-N′-methylurea

62.2 mg (0.2 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended in 0.4 ml of DMF, and 11.4 mg (0.2 mmol) of methylisocyanate are added at room temperature. The mixture is stirredovernight, filtered and purified by preparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 400 μl of DMF solution

Yield: 45.9 mg (62.3% of theory) of product

Mass spectrum: molecular mass calculated: 368, found [M+H]⁺=369.2

Example 12N-(2-{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfanyl}ethyl)-N′-methylurea

62.2 mg (0.2 mmol) of2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrileare suspended in 0.4 ml of DMF, and 14.2 mg (0.2 mmol) of ethylisocyanate are added at room temperature. The mixture is stirredovernight, filtered and purified by preparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 400 μl of DMF solution

Yield: 37.6 mg (49.2% of theory) of product

Mass spectrum: molecular mass calculated: 382, found [M+H]⁺=383.2

Example 133,5-Dicyano-4-(3,5-dichloro-4-hydroxyphenyl)-2-carbamoylmethyl-6-amino-pyridine

337.2 mg (1 mmol) of2-amino-4-(3,5-dichloro-4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrileand 207 mg (1.5 mmol) of bromoacetamide are dissolved in 4 ml of DMF,336 mg (4 mmol) of NaHCO₃ are added and the mixture is stirred at RT for8 hours. The mixture is diluted with water and washed with ethylacetate. The aqueous phase is acidified with 1N HCl and the resultingcrystals are filtered off with suction and dried.

Yield: 180 mg (45.7% of theory) of product

Mass spectrum: molecular mass calculated: 393, found [M+H]⁺=394.1

Example 142-[(6-Amino-3,5-dicyano-4-{4-[(4-methylpiperazino)sulfonyl]phenyl}-2-pyridinyl)sulfanyl]acetamide

84 mg (0.163 mmol) of2-amino-4-{4-[(4-methylpiperazino)sulfonyl]phenyl}-6-sulfanyl-3,5-pyridinedicarbonitrileN-methylmorpholinium salt together with 53.3 mg (0.244 mmol) ofbromoacetamide and 54.7 mg (0.65 mmol) of NaHCO₃ are stirred in 0.5 mlof DMF overnight. After filtration, the reaction solution is initiallypurified by preparative HPLC. The isolated fraction is reconcentratedunder reduced pressure and the residue is purified by preparativethin-layer chromatography.

Yield: 14 mg (18.2% of theory) of product

Mass spectrum: molecular mass calculated: 471, found [M+H]⁺=472.1

Example 152-({6-Amino-3,5-dicyano-4-[4-(piperidinosulfonyl)phenyl]-2-pyridinyl}-sulfanyl)acetamide

82 mg (0.164 mmol) of2-amino-4-{4-(piperidinosulfonyl)phenyl}-6-sulfanyl-3,5-pyridinedicarbonitrileN-methylmorpholinium salt together with 53.5 mg (0.246 mmol) ofbromoacetamide and 55 mg (0.65 mmol) of NaHCO₃ are stirred in 0.5 ml ofDMF overnight. After filtration, the reaction solution is purified bypreparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15 μ 10×20 mm

Wavelength: 220 mm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10%; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 400 μl of DMF solution

Yield: 42.8 mg (57.2% of theory) of product

NMR [400 MHz, DMSO-d₆]: 1.4 m (2H), 1.6 m (4H), 3.0 tr (4H), 3.9 s (2H),7.25 s (1H), 7.5 s (1H), 7.8 d (2H), 7.9 d (2H), 8.1 s broad (2H)

Example 162-({6-Amino-3,5-dicyano-4-[4-(morpholinosulfonyl)phenyl]-2-pyridinyl}-sulfanyl)acetamide

90 mg (0.179 mmol) of2-amino-4-{4-(morpholinosulfonyl)phenyl}-6-sulfanyl-3,5-pyridinedicarbonitrileN-methylmorpholinium salt together with 58.5 mg (0.269 mmol) ofbromoacetamide and 60 mg (0.71 mmol) of NaHCO₃ are stirred in 0.5 ml ofDMF overnight. After filtration, the reaction solution is purified bypreparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 mm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10%; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 400 μl of DMF solution

Yield: 43.7 mg (53.2% of theory) of product

NMR[400 MHz, DMSO-d₆]: 2.9 tr (4H), 3.65 tr (4H), 3.9 s (2H), 7.25 s(1H), 7.5 s (1H), 7.85 d (2H), 7.95 d (2H), 8.15 s broad (2H)

Example 172-(4-{2-amino-6-[(2-amino-2-oxoethyl)sulfanyl]-3,5-dicyano-4-pyridinyl}-phenoxy)aceticacid

135 mg (0.316 mmol) of2-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)-phenoxy]acetic acidN-methylmorpholinium salt together with 103.3 mg (0.474 mmol) ofbromoacetamide and 106.1 mg (1.263 mmol) of NaHCO₃ are stirred in 0.5 mlof DMF overnight. After filtration, the reaction solution is prepurifiedby preparative HPLC. The isolated fraction is reconcentrated underreduced pressure and the residue is purified by preparative thin-layerchromatography.

Yield: 14 mg (11.6% of theory) of product

Mass spectrum: molecular mass calculated: 383, found [M+Na]⁺=406.2

Example 184-{2-Amino-6-[(2-amino-2-oxoethyl)sulfanyl]-3,5-dicyano-4-pyridinyl}-benzoicacid

72 mg (0.18 mmol) of2-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)benzoic acidN-methylmorpholinium salt together with 59.2 mg (0.27 mmol) ofbromoacetamide and 60.9 mg (0.72 mmol) of NaHCO₃ are stirred in 0.5 mlof DMF overnight. After filtration, the reaction solution is prepurifiedby preparative HPLC. The isolated fraction is reconcentrated underreduced pressure and the residue is purified by preparative thin-layerchromatography.

Yield: 11 mg (17.2% of theory) of product

Mass spectrum: molecular mass calculated: 353, found [M+H]⁺=353.9

Example 19 Methyl4-{2-amino-6-[(2-amino-2-oxoethyl)sulfanyl]-3,5-dicyano-4-pyridinyl}-benzoate

89 mg (0.216 mmol) of methyl4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)-benzoateN-methylmorpholinium salt together with 70.7 mg (0.324 mmol) ofbromoacetamide and 72.7 mg (0.86 mmol) of NaHCO₃ are stirred in 0.5 mlof DMF overnight. After filtration, the reaction solution is purified bypreparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 mm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10%; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 400 μl of DMF solution

Yield: 40.4 mg (50.8% of theory) of product

NMR [400 MHz, DMSO-d₆]: 3.9 s (2H), 7.25 s (1H), 7.5 s (1H), 7.7 d (2H),8.1 d (2H), 8.1 s broad (2H)

Example 202-({4-[4-(Acetylamino)phenyl]-6-amino-3,5-dicyano-2-pyridinyl}sulfanyl)-acetamide

44 mg (0.11 mmol) ofN-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)phenyl]-acetamideN-methylmorpholinium salt together with 35 mg (0.16 mmol) ofbromoacetamide and 36 mg (0.43 mmol) of NaHCO₃ are stirred in 0.5 ml ofDMF overnight. After filtration, the reaction solution was purified bypreparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 mm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10%; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 400 μl of DMF solution

Yield: 18.3 mg (46.6% of theory) of product

NMR [400 MHz, DMSO-d₆]: 2.1 s (3H), 3.9 s (2H), 7.25 s (1H), 7.5 d (3H),7.7 d (2H), 8.0 s broad (2H), 10.25 s (1H)

Example 212-Amino-6-[(2-hydroxyethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile

26.8 mg (0.1 mmol) of2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile aredissolved in 0.2 ml of dimethylformamide. 20 mg (0.238 mmol) of solidsodium bicarbonate are added, followed by a solution of 18.74 mg (0.15mmol) of 2-bromoethanol in 0.06 ml of dimethylformamide. The reactionmixture is shaken overnight and, after filtration, purified bypreparative HPLC.

HPLC Conditions:

Column: GROM-SIL 120 ODS 4 HE 5μ 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 1.75 min. 10% A; 5.5 min. 90% A; 8 min. 90% A;    -   8.1 min. 10% A; 9 min. 10% A

Injection volume: 300 μl of DMSO solution

Retention time: 3.97 min

Yield: 14.1 mg (45.1% of theory)

Mass spectrum: molecular mass calculated: 312, found [M+H]⁺=313

Example 22

1. Step:

N-[4-(2,2-Dicyanovinyl)phenyl]acetamide

32.6 g (0.2 mol) of 4-acetaminobenzaldehyde and 13.74 g (0.208 mol) ofmalononitrile are initially charged in 140 ml of ethanol, and 24 dropsof piperidine are added. The mixture is stirred at reflux for 30 min.After cooling, the crystals are filtered off with suction and dried.

Yield: 38.6 g (90.6% of theory) of product

Mass spectrum: molecular mass calculated: 211, found [M+H]⁺=212

2. Step

N-{4-[2-Amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}acetamide

19 g (0.09 mol) of N-[4-(2,2-dicyanovinyl)phenyl]acetamide, 5.95 g (0.09mol) of malononitrile and 9.91 g (0.09 mol) of thiophenol are initiallycharged in 120 ml of ethanol, and 0.4 ml of triethylamine are added. Themixture is stirred at reflux for 2 h, during which the productcrystallizes. After cooling, the product is filtered off with suctionand dried under reduced pressure.

Yield: 10.25 g (29.6% of theory) of product

Mass spectrum: molecular mass calculated: 385, found [M+H]⁺=386

3. Step

N-[4-(2-Amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)phenyl]acetamide

Under argon, 1.16 g (3 mmol) ofN-{4-[2-amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}-acetamideare dissolved in 10 ml of DMF, 0.78 g (10 mmol) of sodium sulfide areadded and the mixture is stirred at 80° C. for 2 h. 20 ml of 1N HCl arethen added and the resulting crystals are filtered off with suction anddried under reduced pressure.

Yield: 428 mg (46.1% of theory) of product

Mass spectrum: molecular mass calculated: 309, found [M+H]⁺=310.1

4. Step

2-[({4-[4-(Acetylamino)phenyl]-6-amino-3,5-dicyano-2-pyridinyl}sulfanyl)-methyl]-1H-imidazol-1-iumtrifluoracetate

309 mg (1 mmol) ofN-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)phenyl]-acetamide, 241mg (1 mmol) of 2-(bromomethyl)-1H-imidazole hydrobromide and 336 mg (4mmol) of NaHCO₃ in 2 ml of DMF are stirred at RT. After 2 h, 4 to 5 mlof water are added and the beige crystals are filtered off with suctionand dried under reduced pressure. The crystals (310 mg) are dissolved inDMSO and purified by prep. HPLC using 9 injections. The correspondingfraction is concentrated under reduced pressure and the crystallineresidue is suspended in water, filtered off with suction and dried underreduced pressure.

HPLC Conditions:

Column: Kromasil 100 C18 5 μm 50×20 mm

Precolumn: GROM-SIL ODS 4 HE 15μ 10×20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A=acetonitrile+0.1% trifluoroacetic acid

-   -   B=water+0.1% trifluoroacetic acid    -   0 min: 10% A; 2 min. 10% A; 6 min. 90% A; 7 min. 90% A;    -   7.1 min. 10% A; 8 min. 10% A

Injection volume: 500 μl of DMSO solution

Retention time: 3.6 min

Yield: 234 mg (60% of theory) of product

Mass spectrum: molecular mass calculated: 389, found [M+H]⁺=390.1

¹H-NMR (300 MHz, DMSO-d₆): δ=2.1 s (3H), 4.7 s (1H), 7.4 d (2H), 7.55 s(1H), 7.7 d (2H), 8.1 s broad (2H), 10.25 s (1H), 14.2 s broad (1H)

The compounds listed in the tables below (examples A 1 to A 377, A 378to A 413 and B 1 to B 375) were prepared analogously to the proceduresgiven above. Identity and purity of the compounds was demonstrated byLC-MS.

The compounds of examples A 1 to A 413 were either isolated as crystalsor, if they did not crystallize directly from the reaction solution,purified by preparative HPLC.

The compounds of examples B 1 to B 375 were prepared on a 10 μmol scale,analogously to the procedures above. These compounds were purified andidentified by a preparative HPLC-MS system.

In the tables below, structures having a group —N— are in each caseunderstood to contain a group —NH— and structures having a group —N arein each case to be understood as containing a group —NH₂. StartingMaterial Ex. No. Product A A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

A73

A74

A75

A76

A77

A78

A79

A80

A81

A82

A83

A84

A85

A86

A87

A88

A89

A90

A91

A92

A93

A94

A95

A96

A97

A98

A99

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

A111

A112

A113

A114

A115

A116

A117

A118

A119

A120

A121

A122

A123

A124

A125

A126

A127

A128

A129

A130

A131

A132

A133

A134

A135

A136

A137

A138

A139

A140

A141

A142

A143

A144

A145

A146

A147

A148

A149

A150

A151

A152

A153

A154

A155

A156

A157

A158

A159

A160

A161

A162

A163

A164

A165

A166

A167

A168

A169

A170

A171

A172

A173

A174

A175

A176

A177

A178

A179

A180

A181

A182

A183

A184

A185

A186

A187

A188

A189

A190

A191

A192

A193

A194

A195

A196

A197

A198

A199

A200

A201

A202

A203

A204

A205

A206

A207

A208

A209

A210

A211

A212

A213

A214

A215

A216

A217

A218

A219

A220

A221

A222

A223

A224

A225

A226

A227

A228

A229

A230

A231

A232

A233

A234

A235

A236

A237

A238

A239

A240

A241

A242

A243

A244

A245

A246

A247

A248

A249

A250

A251

A252

A253

A254

A255

A256

A257

A258

A259

A260

A261

A262

A263

A264

A265

A266

A267

A268

A269

A270

A271

A272

A273

A274

A275

A276

A277

A278

A279

A280

A281

A282

A283

A284

A285

A286

A287

A288

A289

A290

A291

A292

A293

A294

A295

A296

A297

A298

A299

A300

A301

A302

A303

A304

A305

A306

A307

A308

A309

A310

A311

A312

A313

A314

A315

A316

A317

A318

A319

A320

A321

A322

A323

A324

A325

A326

A327

A328

A329

A330

A331

A332

A333

A334

A335

A336

A337

A338

A339

A340

A341

A342

A343

A344

A345

A346

A347

A348

A349

A350

A351

A352

A353

A354

A355

A356

A357

A358

A359

A360

A361

A362

A363

A364

A365

A366

A367

A368

A369

A370

A371

A372

A373

A374

A375

A376

A377

Starting material Molecular mass [M + H]+ Yield Ex. No. B calculatedfound (% of theory) A1

325 326 57.5 A2

326 327 7.0 A3

326 327 52.7 A4

339 340 67.5 A5

340 341 60.8 A6

354 355 53.6 A7

366 367 30.0 A8

386 387 57.2 A9

394 395 12.2 A10

404 405 39.3 A11

415 416 58.2 A12

430 431 25.1 A13

446 447 28.1 A14

456 457 29.6 A15

470 471 62.2 A16

342 343 54.0 A17

352 353 73.8 A18

402 403 65.6 A19

416 417 51.9 A20

341 342 29.7 A21

354 355 84.4 A22

355 356 10.0 A23

355 356 35.2 A24

368 369 77.1 A25

369 370 70.9 A26

383 384 68.1 A27

395 396 60.2 A28

415 416 58.0 A29

423 424 31.2 A30

433 434 36.2 A31

444 445 51.1 A32

459 460 46.7 A33

475 476 49.7 A34

485 486 47.1 A35

499 500 64.0 A36

507 508 37.5 A37

521 522 61.5 A38

371 372 63.8 A39

381 382 50.3 A40

431 432 40.8 A41

445 446 71.9 A42

445 446 32.6 A43

312 313 60.8 A44

325 326 78.4 A45

326 327 13.9 A46

326 327 17.8 A47

339 340 89.6 A48

340 341 77.6 A49

354 355 56.2 A50

366 367 47.5 A51

386 387 36.5 A52

394 395 20.5 A53

404 405 58.8 A54

415 416 18.3 A55

430 431 29.8 A56

446 447 42.2 A57

456 457 9.2 A58

478 479 13.9 A59

492 493 66.3 A60

342 343 73.6 A61

352 353 68.1 A62

402 403 41.2 A63

416 417 52.1 A64

416 417 52.6 A65

314 315 62.7 A66

327 328 58.0 A67

328 329 17.1 A68

328 329 53.9 A69

341 342 57.7 A70

342 343 35.6 A71

356 357 49.7 A72

360 361 43.3 A73

368 369 14.7 A74

388 389 17.5 A75

417 418 31.1 A76

458 459 19.5 A77

472 473 41.8 A78

480 481 32.9 A79

494 495 29.0 A80

344 345 45.6 A81

354 355 37.2 A82

404 405 37.6 A83

418 419 63.3 A84

418 419 21.5 A85

331 332 71.3 A86

344 345 66.9 A87

345 346 76.3 A88

358 359 83.8 A89

359 360 89.7 A90

373 374 70.5 A91

385 386 12.2 A92

405 406 84.0 A93

413 414 12.1 A94

423 424 23.6 A95

434 435 67.3 A96

488 489 67.4 A97

496 497 90.2 A98

510 511 55.7 A99

361 362 103.1 A100

371 372 48.3 A101

421 422 97.9 A102

435 436 51.7 A103

435 436 63.7 A104

296 297 82.0 A105

309 310 75.6 A106

310 311 72.5 A107

323 324 84.4 A108

324 325 67.8 A109

338 339 71.8 A110

342 343 44.7 A111

350 351 18.5 A112

370 371 73.2 A113

378 379 46.8 A114

388 389 91.4 A115

399 400 17.5 A116

414 415 16.7 A117

430 431 31.4 A118

454 455 58.4 A119

462 463 77.1 A120

476 477 13.0 A121

326 327 89.8 A122

336 337 69.3 A123

386 387 73.2 A124

400 401 66.9 A125

400 401 74.2 A126

331 332 72.6 A127

344 345 68.1 A128

345 346 70.2 A129

358 359 72.4 A130

359 360 44.3 A131

373 374 57.7 A132

377 378 17.2 A133

385 386 14.0 A134

405 406 8.9 A135

413 414 17.2 A136

423 424 12.8 A137

434 435 10.1 A138

448 449 10.0 A139

474 475 52.1 A140

488 489 52.3 A141

496 497 50.2 A142

510 511 43.5 A143

361 362 56.0 A144

435 436 3.7 A145

435 436 67.4 A146

331 332 64.1 A147

344 345 70.7 A148

358 359 72.7 A149

359 360 58.8 A150

373 374 56.3 A151

377 378 55.5 A152

385 386 64.2 A153

405 406 32.4 A154

413 414 55.7 A155

423 424 53.9 A156

434 435 74.9 A157

448 449 69.0 A158

464 465 72.0 A159

474 475 73.0 A160

488 489 75.2 A161

496 497 75.5 A162

510 511 67.4 A163

371 372 75.2 A164

421 422 57.7 A165

435 436 71.3 A166

435 436 54.0 A167

326 327 50.9 A168

339 340 76.3 A169

353 354 50.4 A170

372 373 30.6 A171

418 419 13.6 A172

430 431 63.8 A173

444 445 26.2 A174

460 461 32.2 A175

470 471 96.9 A176

484 485 18.2 A177

492 493 78.5 A178

356 357 17.1 A179

366 367 31.1 A180

416 417 80.0 A181

430 431 66.2 A182

430 431 73.6 A183

310 311 28.4 A184

323 324 39.3 A185

324 325 41.9 A186

337 338 40.9 A187

338 339 11.5 A188

352 353 29.2 A189

356 357 51.9 A190

364 365 77.4 A191

414 415 51.8 A192

428 429 58.2 A193

444 445 58.2 A194

454 455 29.5 A195

468 469 43.8 A196

476 477 51.7 A197

490 491 73.9 A198

340 341 37.9 A199

350 351 80.8 A200

400 401 48.4 A201

414 415 20.7 A202

414 415 61.0 A203

341 342 55.4 A204

354 355 38.4 A205

368 369 70.6 A206

369 370 49.5 A207

383 384 65.5 A208

395 396 14.2 A209

415 416 22.9 A210

433 434 40.8 A211

444 445 70.2 A212

459 460 21.6 A213

475 476 57.5 A214

485 486 41.5 A215

499 500 43.1 A216

507 508 56.2 A217

371 372 62.5 A218

381 382 39.9 A219

431 432 55.6 A220

445 446 32.6 A221

352 353 61.3 A222

365 366 80.2 A223

366 367 73.1 A224

379 380 81.7 A225

380 381 71.0 A226

394 395 65.9 A227

398 399 76.3 A228

407 408 79.7 A229

427 428 40.8 A230

434 435 22.1 A231

444 445 9.7 A232

456 457 15.6 A233

470 471 43.7 A234

486 487 71.1 A235

496 497 96.4 A236

510 511 84.6 A237

518 519 41.7 A238

532 533 28.8 A239

382 383 83.7 A240

392 393 54.8 A241

443 444 75.0 A242

457 458 50.2 A243

457 458 44.9 A244

352 353 54.5 A245

369 370 85.5 A246

370 371 60.7 A247

384 385 59.1 A248

386 387 79.7 A249

370 371 51.6 A250

370 371 49.4 A251

448 449 70.4 A252

426 427 39.0 A253

324 325 66.9 A254

328 329 90.1 A255

341 342 114.5 A256

342 343 70.7 A257

356 357 77.7 A258

374 375 87.1 A259

342 343 85.3 A260

342 343 73.3 A261

419 420 91.3 A262

397 398 66.2 A263

350 351 50.5 A264

368 369 49.1 A265

382 383 58.6 A266

400 401 53.4 A267

368 369 48.9 A268

368 369 31.8 A269

381 382 30.2 A270

423 424 17.0 A271

338 339 71.2 A272

342 343 50.8 A273

355 356 96.0 A274

356 357 69.0 A275

370 371 80.5 A276

372 373 85.4 A277

356 357 69.3 A278

356 357 58.9 A279

434 435 84.4 A280

411 412 80.2 A281

338 339 60.6 A282

342 343 59.3 A283

356 357 62.0 A284

370 371 55.3 A285

388 389 59.0 A286

356 357 43.2 A287

356 357 46.6 A288

434 435 62.5 A289

411 412 24.5 A290

421 422 100.6 A291

438 439 75.4 A292

453 454 58.8 A293

439 440 50.2 A294

352 353 68.7 A295

356 357 73.5 A296

369 370 92.9 A297

370 371 78.6 A298

384 385 71.0 A299

402 403 84.2 A300

386 387 100.9 A301

370 371 100.4 A302

370 371 82.3 A303

448 449 82.0 A304

426 427 60.2 A305

324 325 26.8 A306

328 329 33.8 A307

341 342 43.1 A308

342 343 34.2 A309

356 357 30.9 A310

374 375 34.7 A311

358 359 41.0 A312

342 343 33.3 A313

342 343 25.1 A314

419 420 30.3 A315

355 356 36.3 A316

397 398 30.7 A317

368 369 68.9 A318

372 373 77.6 A319

385 386 107.4 A320

386 387 64.2 A321

402 403 88.7 A322

386 387 73.8 A323

386 387 74.5 A324

464 465 83.3 A325

442 443 85.6 A326

322 323 53.0 A327

326 327 19.3 A328

339 340 88.1 A329

340 341 77.3 A330

354 355 68.3 A331

372 373 59.3 A332

356 357 75.2 A333

340 341 47.0 A334

340 341 60.5 A335

418 419 80.5 A336

395 396 74.6 A337

354 355 56.4 A338

371 372 47.4 A339

372 373 68.5 A340

386 387 81.0 A341

404 405 77.1 A342

388 389 64.1 A343

372 373 65.5 A344

372 373 67.9 A345

450 451 77.0 A346

427 428 77.2 A347

368 369 69.5 A348

372 373 10.7 A349

385 386 46.2 A350

386 387 75.6 A351

400 401 31.7 A352

418 419 90.8 A353

402 403 92.4 A354

386 387 73.2 A355

386 387 55.6 A356

464 465 85.4 A357

339 340 58.9 A358

353 354 89.1 A359

367 368 61.5 A360

369 370 65.2 A361

353 354 61.7 A362

431 432 53.9 A363

408 409 61.7 A364

317 318 35.9 A365

334 335 24.5 A366

349 350 41.2 A367

367 368 45.2 A368

335 336 50.1 A369

343 344 75.6 A370

347 348 89.4 A371

360 361 81.7 A372

361 362 89.0 A373

375 376 60.8 A374

393 394 69.5 A375

361 362 21.9 A376

361 362 56.5 A377

438 439 90.7

Starting material Ex. No. Product A A378

A379

A380

A381

A382

A383

A384

A385

A386

A387

A388

A389

A390

A391

A392

A393

A394

A395

A396

A397

A398

A399

A400

A401

A402

A403

A404

A405

A406

A407

A408

A409

A410

A411

A412

A413

Starting Molar material mass [M + H]+ Yield (% Ex. No. B calculatedfound of theory) A378

476 477 40.3 A379

462 463 16.4 A380

446 447 71.7 A381

388 389 74.2 A382

336 337 76.4 A383

376 377 68.3 A384

376 377 66.4 A385

388 389 64.9 A386

393 394 57.7 A387

431 432 23.4 A388

400 401 46.5 A389

456 457 5.5 A390

386 387 62.9 A391

403 404 60.2 A392

416 417 18.0 A393

383 384 55.6 A394

424 425 56.5 A395

527 528 67.8 A396

367 368 13.6 A397

343 344 23.6 A398

384 385 15.6 A399

367 368 72.4 A400

367 368 7.1 A401

408 409 78.1 A402

511 512 45.0 A403

380 381 21.8 A404

399 400 47.3 A405

353 354 56.6 A406

367 368 43.3 A407

367 368 49.8 A408

364 365 68.6 A409

446 447 57.3 A410

377 378 15.5 A411

332 333 35.4 A412

310 311 86.4 A413

326 327 46.4

Molecular Ex. No. Product weight B1

419 B2

465 B3

439 B4

465 B5

450 B6

455 B7

435 B8

498 B9

419 B10

484 B11

406 B12

406 B13

541 B14

481 B15

423 B16

473 B17

474 B18

450 B19

515 B20

439 B21

474 B22

430 B23

434 B24

443 B25

507 B26

406 B27

469 B28

515 B29

540 B30

476 B31

463 B32

497 B33

461 B34

541 B35

562 B36

486 B37

473 B38

373 B39

434 B40

560 B41

433 B42

474 B43

451 B44

515 B45

419 B46

556 B47

369 B48

631 B49

550 B50

492 B51

545 B52

515 B53

479 B54

484 B55

381 B56

527 B57

417 B58

396 B59

397 B60

460 B61

373 B62

415 B63

357 B64

400 B65

384 B66

430 B67

430 B68

400 B69

400 B70

463 B71

384 B72

371 B73

371 B74

371 B75

447 B76

388 B77

438 B78

415 B79

408 B80

473 B81

371 B82

434 B83

481 B84

442 B85

428 B86

463 B87

528 B88

452 B89

438 B90

338 B91

399 B92

398 B93

417 B94

481 B95

384 B96

334 B97

516 B98

457 B99

481 B100

445 B101

399 B102

456 B103

346 B104

382 B105

361 B106

362 B107

426 B108

338 B109

380 B110

322 B111

379 B112

435 B113

419 B114

465 B115

465 B116

498 B117

419 B118

406 B119

406 B120

406 B121

481 B122

423 B123

473 B124

450 B125

443 B126

507 B127

469 B128

515 B129

476 B130

562 B131

486 B132

473 B133

373 B134

434 B135

451 B136

515 B137

415 B138

419 B139

369 B140

492 B141

484 B142

427 B143

381 B144

417 B145

396 B146

397 B147

460 B148

373 B149

357 B150

414 B151

416 B152

416 B153

416 B154

444 B155

453 B156

550 B157

573 B158

444 B159

462 B160

425 B161

494 B162

602 B163

391 B164

427 B165

407 B166

471 B167

424 B168

430 B169

461 B170

435 B171

461 B172

445 B173

451 B174

430 B175

430 B176

493 B177

414 B178

401 B179

401 B180

401 B181

477 B182

418 B183

468 B184

469 B185

445 B186

435 B187

425 B188

430 B189

439 B190

503 B191

401 B192

425 B193

464 B194

511 B195

472 B196

458 B197

493 B198

457 B199

558 B200

482 B201

468 B202

368 B203

430 B204

429 B205

469 B206

447 B207

511 B208

364 B209

546 B210

487 B211

475 B212

480 B213

493 B214

479 B215

423 B216

429 B217

486 B218

605 B219

376 B220

412 B221

391 B222

392 B223

456 B224

410 B225

352 B226

409 B227

457 B228

441 B229

487 B230

487 B231

457 B232

457 B233

441 B234

427 B235

427 B236

427 B237

503 B238

444 B239

494 B240

471 B241

456 B242

465 B243

529 B244

427 B245

490 B246

498 B247

485 B248

519 B249

584 B250

456 B251

455 B252

473 B253

537 B254

441 B255

390 B256

572 B257

513 B258

567 B259

501 B260

443 B261

455 B262

512 B263

402 B264

439 B265

417 B266

418 B267

482 B268

394 B269

436 B270

414 B271

461 B272

398 B273

445 B274

445 B275

429 B276

435 B277

414 B278

414 B279

477 B280

398 B281

385 B282

385 B283

385 B284

461 B285

402 B286

452 B287

453 B288

429 B289

419 B290

409 B291

414 B292

423 B293

487 B294

385 B295

409 B296

448 B297

495 B298

456 B299

443 B300

477 B301

542 B302

466 B303

452 B304

352 B305

414 B306

413 B307

453 B308

431 B309

495 B310

398 B311

348 B312

611 B313

530 B314

471 B315

525 B316

459 B317

407 B318

401 B319

413 B320

470 B321

360 B322

396 B323

375 B324

376 B325

440 B326

414 B327

352 B328

394 B329

336 B330

393 B331

435 B332

419 B333

465 B334

465 B335

435 B336

435 B337

419 B338

406 B339

406 B340

406 B341

481 B342

423 B343

473 B344

434 B345

443 B346

406 B347

469 B348

515 B349

476 B350

562 B351

486 B352

473 B353

373 B354

434 B355

433 B356

451 B357

515 B358

419 B359

369 B360

550 B361

515 B362

479 B363

484 B364

422 B365

433 B366

490 B367

381 B368

417 B369

396 B370

397 B371

460 B372

373 B373

415 B374

357 B375

414

1. A compound of the formula (I)

wherein: R¹, R², R³ are identical or different and independently of oneanother are selected from the group consisting of the followingsubstituents: hydrogen; hydroxyl; optionally substituted (C₁-C₈)-alkyl;optionally substituted (C₆-C₁₀)-aryl; optionally substituted(C₁-C₈)-alkoxy; —O—(CH₂)_(n)—CH═CH₂ where n=0, 1 or 2; halogen; nitro;cyano; —C(O)—R⁵; —C(O)—NR⁶R⁷; —NR⁶R⁷; —NR⁶—C(O)—R⁸; —O—C(O)—R⁸;—SO₂—NR⁶R⁷; and —NR⁶—SO₂R⁸, where: R⁵ denotes: hydrogen; hydroxyl;optionally substituted (C₁-C₈)-alkyl; optionally substituted(C₃-C₇)-cycloalkyl; optionally substituted (C₁-C₈)-alkoxy; optionallysubstituted (C₆-C₁₀)-aryl; optionally substituted (C₆-C₁₀)-aryloxy; or—O—(CH₂)_(n)—[(C₆-C₁₀)-aryl] where n=1, 2 or 3, where the (C₆-C₁₀)-arylgroup may be fused via two adjacent ring atoms to optionally substituted(C₄-C₇)-cycloalkyl, or R⁵ represents a 5- to 7-membered saturated orunsaturated heterocycle which may be mono- or polysubstituted by an oxogroup (═O); halogen; optionally substituted (C₁-C₈)-alkyl; nitro; cyano;hydroxyl; optionally substituted (C₆-C₁₀)-aryl; or by (C₁-C₈)-alkoxy, orR⁵ represents optionally substituted 5- to 6-membered heteroaryl havingup to 3 heteroatoms from the group consisting of N, O and S, where theheterocycle and the heteroaryl ring may each optionally be fused via twoadjacent ring atoms to optionally substituted (C₆-C₁₀)-aryl oroptionally substituted (C₄-C₇)-cycloalkyl, and R⁶ and R⁷ are identicalor different and represent hydrogen; optionally substituted(C₁-C₈)-alkyl; optionally substituted (C₆-C₁₀)-aryl; or representoptionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S or R⁶ and R⁷together with the nitrogen atom to which they are optionally attachedform a 5- to 7-membered saturated or unsaturated heterocycle having upto 3 heteroatoms from the group consisting of N, O and S, which mayoptionally be mono- or polysubstituted by identical or differentsubstituents from the group consisting of an oxo group (═O); halogen;(C₁-C₈)-alkyl; nitro; cyano; hydroxyl; (C₆-C₁₀)-aryl; and(C₁-C₈)-alkoxy, and R⁸ represents hydroxyl; NR⁶R⁷ where R⁶ and R⁷ are asdefined above; optionally substituted (C₁-C₈)-alkyl; (C₁-C₈)-alkoxy;optionally substituted (C₆-C₁₀)-aryl; (C₆-C₁₀)-aryloxy; or—O—(CH₂)_(n)—[(C₆-C₁₀)-aryl] where n=1, 2 or 3, and R⁴ representsstraight-chain or branched (C₁-C₈)-alkyl or (C₂-C₈)-alkenyl which areoptionally mono- or polysubstituted by hydroxyl; halogen; cyano;—C(O)—R⁵ where R⁵ is as defined above; —C(O)—NR⁶R⁷ where R⁶ and R⁷ areas defined above; —NR⁶R⁷ where R⁶ and R⁷ are as defined above;—NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above; —SO₂—NR⁶R⁷ where R⁶and R⁷ are as defined above; —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are as definedabove; —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is as definedabove; (C₁-C₈)-alkoxy; optionally substituted (C₆-C₁₀)-aryloxy;optionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S; optionallysubstituted (C₆-C₁₀)-aryl; or by a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the groupconsisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); halogen; (C₁-C₈)-alkyl; nitro; cyano;hydroxyl; (C₆-C₁₀)-aryl; or by (C₁-C₈)-alkoxy, where the heterocycle andthe heteroaryl ring may each optionally be fused via two adjacent ringatoms to optionally substituted (C₆-C₁₀)-aryl, or R⁴ represents a 5- to7-membered saturated or unsaturated heterocycle having up to 3heteroatoms from the group consisting of N, O and S, which mayoptionally be mono- or polysubstituted by identical or differentsubstituents from the group consisting of an oxo group (═O); halogen;(C₁-C₈)-alkyl; nitro; cyano; hydroxyl; (C₆-C₁₀)-aryl; or by(C₁-C₈)-alkoxy, and which may optionally be fused via two adjacent ringatoms to optionally substituted (C₆-C₁₀)-aryl or optionally substituted(C₄-C₇)-cycloalkyl, or a tautomer, salt, hydrate, or alkoxide thereof,except for the following compounds of the formula (I), in which theradicals R¹, R², R³ and R⁴ are as defined below: R¹=R²=H; R³=para-OH;R⁴=—CH₂-Z where Z=CN, C(O)—OC₂H₅, 4-Br—C₆H₄—CO, 4-n-butyl-C₆H₄—CO, H,C₆H₅, C(O)—O—CH₂—C₆H₅, C(O)—OCH₃, C(O)—OH,2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO, 3-Br—C₆H₄—CO,4-C₆H₅—C₆H₄—CO, 4—CH₃—C₆H₄—CO, 3,4-Cl₂-C₆H₃—CO; R¹=R²=H; R³=meta-OH;R⁴=—CH₂-Z where Z=4-Br—C₆H₄—NH—CO, 2-oxo-benzo-pyranyl-3-carbonyl,4-Cl—C₆H₄—CO; R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z whereZ=4—CH₃—C₆H₄—CO, H, 2-oxo-benzopyranyl-3-carbonyl, (CH₂)₃—CH₃,4-C₆H₅—C₆H₄; R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃, CN, 2-naphthyl; R¹=R²=H;R³=para-butoxy; R⁴=—CH₂-Z where Z=4-Cl—C₆H₅, C(O)—OCH₃, C(O)—C₆H₅,CH═CH₂, C(O)—NH₂, H, 4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO, C(O)—OC₂H₅,C(O)—O—CH₂—C₆H₅, 2-oxo-benzopyranyl-3-carbonyl, C(O)—NH—C₆H₅, CN;R¹=R²=H; R³=para-bromo; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO,C(O)—NH₂, C(O)—OCH₃, 4-Cl—C₆H₅, 4-Br—C₆H₄—NH—CO; R¹=R²=H;R³=meta-fluoro; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO, C(O)—NH₂,C(O)—O—CH₂—C₆H₅, CN; R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z whereZ=2-naphthyl, CH₃; R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Z where Z=2-naphthyl,CH₃; R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.
 2. The compound of theformula (I) as claimed in claim 1, wherein: R¹, R², R³ are identical ordifferent and independently of one another are selected from the groupconsisting of the following substituents: hydrogen; hydroxyl; optionallysubstituted (C₁-C₆)-alkyl; optionally substituted phenyl or naphthyl;optionally substituted (C₁-C₆)-alkoxy; —O—(CH₂)_(n)—CH═CH₂ where n=1 or2; fluorine, chlorine, bromine; nitro; cyano; —C(O)—R⁵; —C(O)—NR⁶R⁷;—NR⁶R⁷; —NR⁶—C(O)—R⁸; —O—C(O)—R⁸; —SO₂—NR⁶R⁷; and —NR⁶—SO₂R⁸, where: R⁵denotes: hydrogen; hydroxyl; optionally substituted (C₁-C₆)-alkyl;optionally substituted (C₃-C₇)-cycloalkyl; optionally substituted(C₁-C₆)-alkoxy; optionally substituted phenyl or naphthyl; optionallysubstituted phenyloxy or naphthyloxy; or —O—(CH₂)_(n)-phenyl where n=1,2 or 3, where the phenyl or naphthyl group may be fused via two adjacentring atoms to optionally substituted (C₄-C₇)-cycloalkyl, or R⁵represents a 5- to 7-membered saturated or unsaturated heterocycle whichmay be mono- or polysubstituted by an oxo group (═O); fluorine,chlorine, bromine; optionally substituted (C₁-C₆)-alkyl; nitro; cyano;hydroxyl; optionally substituted phenyl or naphthyl; or by(C₁-C₆)-alkoxy, or R⁵ represents optionally substituted 5- to 6-memberedheteroaryl having up to 3 heteroatoms from the group consisting of N, Oand S, where the heterocycle and the heteroaryl ring may each optionallybe fused via two adjacent ring atoms to optionally substituted phenyl ornaphthyl or optionally substituted (C₄-C₇)-cycloalkyl, and R⁶ and R⁷ areidentical or different and represent hydrogen; optionally substituted(C₁-C₆)-alkyl; optionally substituted phenyl or naphthyl; or representoptionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S or R⁶ and R⁷together with the nitrogen atom to which they are optionally attachedform a 5- to 7-membered saturated or unsaturated heterocycle having upto 3 heteroatoms from the group consisting of N, O and S, which mayoptionally be mono- or polysubstituted by identical or differentsubstituents from the group consisting of an oxo group (═O); fluorine,chlorine, bromine; (C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl ornaphthyl; and (C₁-C₆)-alkoxy, and R⁸ represents NR⁶R⁷ where R⁶ and R⁷are as defined above; optionally substituted (C₁-C₆)-alkyl;(C₁-C₆)-alkoxy; optionally substituted phenyl or naphthyl; phenyloxy ornaphthyloxy; or —O—(CH₂)_(n)-phenyl where n=1, 2 or 3, and R⁴ representsstraight-chain or branched (C₁-C₆)-alkyl or (C₂-C₆)-alkenyl which areoptionally mono- or polysubstituted by hydroxyl; fluoro, chloro,bromine; cyano; —C(O)—R⁵ where R⁵ is as defined above; —C(O)—NR⁶R⁷ whereR⁶ and R⁷ are as defined above; —NR⁶R⁷ where R⁶ and R⁷ are as definedabove; —NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above; —SO₂—NR⁶R⁷where R⁶ and R⁷ are as defined above; —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are asdefined above; —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is asdefined above; (C₁-C₆)-alkoxy; optionally substituted phenyloxy ornaphthyloxy; optionally substituted 5- to 6-membered heteroaryl havingup to 3 heteroatoms from the group consisting of N, O and S; optionallysubstituted phenyl or naphthyl; or by a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the groupconsisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from thegroup-consisting of an oxo group (═O); fluorine, chlorine, bromine;(C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl or naphthyl; or by(C₁-C₆)-alkoxy, where the heterocycle and the heteroaryl ring may eachoptionally be fused via two adjacent ring atoms to optionallysubstituted phenyl or naphthyl, or R⁴ represents a 5- to 7-memberedsaturated or unsaturated heterocycle having up to 3 heteroatoms from thegroup consisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); fluorine, chlorine, bromine;(C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl or naphthyl; or by(C₁-C₆)-alkoxy and which may optionally be fused via two adjacent ringatoms to optionally substituted phenyl or naphthyl or optionallysubstituted (C₄-C₇)-cycloalkyl, or a tautomer, salt hydrate, or alkoxidethereof, except for the following compounds of the formula (I), in whichthe radicals R¹, R², R³ and R⁴ are as defined below: R¹=R²=H;R³=para-OH; R⁴=—CH₂-Z where Z=CN, C(O)—OC₂H₅, 4-Br—C₆H₄—CO,4-n-butyl-C₆H₄—CO, H, C₆H₅, C(O)—O—CH₂—C₆H₅, C(O)—OCH₃, C(O)—OH,2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO, 3-Br—C₆H₄—CO4-C₆H₅—C₆H₄—CO, 4—CH₃—C₆H₄—CO, 3,4-Cl₂-C₆H₃—CO; R¹=R²=H; R³=meta-OH;R⁴=—CH₂-Z where Z=4-Br—C₆H₄—NH—CO, 2-oxo-benzo-pyranyl-3-carbonyl,4-Cl—C₆H₄—CO; R¹=R²=H; R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z whereZ=4—CH₃—C₆H₄—CO, H, 2-oxo-benzopyranyl-3-carbonyl, (CH₂)₃—CH₃,4-C₆H₅—C₆H₄; R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃, CN, 2-naphthyl; R¹=R²=H;R³=para-butoxy; R⁴=—CH₂-Z where Z=4-Cl—C₆H₅, C(O)—OCH₃, C(O)—C₆H₅,CH═CH₂, C(O)—NH₂, H, 4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO, C(O)—OC₂H₅,C(O)—O—CH₂—C₆H₅, 2-oxo-benzopyranyl-3-carbonyl, C(O) —NH—C₆H₅, CN;R¹=R²=H; R³=para-bromo; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO,C(O)—NH₂, C(O)—OCH₃, 4-Cl—C₆H₅, 4-Br—C₆H₄—NH—CO; R¹=R²=H;R³=meta-fluoro; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—CO, C(O)—NH₂,C(O)—O—CH₂—C₆H₅, CN; R¹=R²=H; R³=para-chloro; R⁴=—CH₂-Z whereZ=2-naphthyl, CH₃; R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Z where Z=2-naphthyl,CH₃; R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.
 3. The compound of theformula (I) as claimed in claim 1, wherein: R¹, R², R³ are identical ordifferent and independently of one another are selected from the groupconsisting of the following substituents: hydrogen; hydroxyl; optionallysubstituted (C₁-C₄)-alkyl; optionally substituted phenyl; optionallysubstituted (C₁-C₄)-alkoxy; —O—(CH₂)_(n)—CH═CH₂ where n=1; fluorine,chlorine; nitro; cyano; —C(O)—R⁵; —C(O)—NR⁶R⁷; —NR⁶R⁷; —NR⁶—C(O)—R⁸;—O—C(O)—R⁸; —SO₂—NR⁶R⁷; and —NR⁶—SO₂R⁸, where: R⁵ denotes: hydrogen;hydroxyl; optionally substituted (C₁-C₄)-alkyl; optionally substituted(C₃-C₇)-cycloalkyl; optionally substituted (C₁-C₄)-alkoxy; optionallysubstituted phenyl; optionally substituted phenyloxy; or—O—(CH₂)_(n)-phenyl where n=1, where the phenyl group may be fused viatwo adjacent ring atoms to optionally substituted (C₅-C₆)-cycloalkyl, orR⁵ represents a 5- to 7-membered saturated or unsaturated heterocyclewhich may be mono- or polysubstituted by an oxo group (═O); fluorine,chlorine; optionally substituted (C₁-C₄)-alkyl; nitro; cyano; hydroxyl;optionally substituted phenyl; or by (C₁-C₄)-alkoxy, or R⁵ representsoptionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S, selected from thegroup consisting of furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl, where theheterocycle and the heteroaryl ring may each optionally be fused via twoadjacent ring atoms to optionally substituted phenyl or optionallysubstituted (C₅-C₆)-cycloalkyl, and R⁶ and R⁷ are identical or differentand represent hydrogen; optionally substituted (C₁-C₄)-alkyl; optionallysubstituted phenyl; or represent optionally substituted 5- to 6-memberedheteroaryl having up to 3 heteroatoms from the group consisting of N, Oand S selected from the group consisting of furanyl, pyrrolyl, thienyl,thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl andpyridazinyl, or R⁶ and R⁷ together with the nitrogen atom to which theyare optionally attached form a 5- to 7-membered saturated or unsaturatedheterocycle having up to 3 heteroatoms from the group consisting of N, Oand S which may optionally be mono- or polysubstituted by identical ordifferent substituents from the group consisting of an oxo group (═O);fluorine, chlorine; (C₁-C₄)-alkyl; nitro; cyano; hydroxyl; phenyl; and(C₁-C₄)-alkoxy, and R⁸ represents NR⁶R⁷ where R⁶ and R⁷ are as definedabove; optionally substituted (C₁-C₄)-alkyl; (C₁-C₄)-alkoxy; optionallysubstituted phenyl; phenyloxy; or —O—(CH₂)_(n)-phenyl where n=1, and R⁴represents straight-chain or branched (C₁-C₄)-alkyl or (C₂-C₄)-alkenylwhich are optionally mono- or polysubstituted by hydroxyl; fluorine,chlorine; cyano; —C(O)—R⁵ where R⁵ is as defined above; —C(O)—NR⁶R⁷where R⁶ and R⁷ are as defined above; —NR⁶R⁷ where R⁶ and R⁷ are asdefined above; —NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above;—SO₂—NR⁶R⁷ where R⁶ and R⁷ are as defined above; —NR⁶—SO₂—R⁸ where R⁶and R⁸ are as defined above; —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 andR⁸ is as defined above; (C₁-C₄)-alkoxy; optionally substitutedphenyloxy; optionally substituted 5- to 6-membered heteroaryl having upto 3 heteroatoms from the group consisting of N, O and S selected fromthe group consisting of furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl; optionallysubstituted phenyl; or by a 5- to 7-membered saturated or unsaturatedheterocycle having up to 3 heteroatoms from the group consisting of N, Oand S, which may optionally be mono- or polysubstituted by identical ordifferent substituents from the group consisting of an oxo group (═O);fluorine, chlorine; (C₁-C₄)-alkyl; nitro; cyano; hydroxyl; phenyl; or by(C₁-C₄)-alkoxy, where the heterocycle and the heteroaryl ring may eachoptionally be fused via two adjacent rings atoms to optionallysubstituted phenyl, or R⁴ represents a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the groupconsisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); fluorine, chlorine; (C₁-C₄)-alkyl;nitro; cyano; hydroxyl; phenyl; or by (C₁-C₄)-alkoxy and which mayoptionally be fused via two adjacent ring atoms to optionallysubstituted phenyl or optionally substituted (C₅-C₆)-cycloalkyl, or atautomer, salt, hydrate, or alkoxide thereof, except for the followingcompounds of the formula (I), in which the radicals R¹, R², R³ and R⁴are as defined below: R¹=R²=H; R³=para-OH; R⁴=—CH₂-Z where Z=CN,C(O)—OC₂H₅, 4-Br—C₆H₄—CO, 4-n-butyl-C₆H₄—CO, H, C₆H₅, C(O)—O—CH₂—C₆H₅,C(O)—OCH₃, C(O)—OH, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO,3-Br—C₆H₄—CO, 4-C₆H₅—C₆H₄—CO, 4—CH₃—C₆H₄—CO, 3,4-Cl₂-C₆H₃—CO; R¹=R²=H;R³=meta-OH; R⁴=—CH₂-Z where Z=4-Br—C₆H₄—NH—CO,2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl—C₆H₄—CO; R¹=R²=H;R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=4—CH₃—C₆H₄—CO, H,2-oxo-benzopyranyl-3-carbonyl, 4-C₆H₅—C₆H₄; R¹=R²=R³=H; R⁴=—CH₂-Z whereZ=CH₃, CN; R¹=R²=H; R³=para-butoxy; R⁴=—CH₂-Z where Z=4-Cl—C₆H₅,C(O)—OCH₃, C(O)—C₆H₅, CH═CH₂, C(O)—NH₂, H, 4-Br—C₆H₄—CO, 4-Cl—C₆H₄—CO,C(O)—OC₂H₅, C(O)—O—CH₂—C₆H₅, 2-oxo-benzopyranyl-3-carbonyl,C(O)—NH—C₆H₅, CN; R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z whereZ=4-Br—C₆H₄—CO, C(O)—NH₂, C(O)—O—CH₂—C₆H₅, CN; R¹=R²=H; R³=para-chloro;R⁴=—CH₂-Z where Z=CH₃; R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Z where Z=CH₃;R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.
 4. The compound of theformula (I) as claimed in any of claims 1 to 3, wherein R¹, R², R³ areidentical or different and independently of one another are selectedfrom the group consisting of the following substituents: hydrogen;hydroxyl; methyl; trifluoromethyl; methoxy; radicals of the formulae—O—CH₂—CH₂—OH, —O—CH₂—COOH or —O—CH₂—CH═CH₂; fluorine, chlorine orbromine; nitro; cyano; —C(O)OH or —C(O)OCH₃; —C(O)NH₂; —NH₂;—NH—C(O)—CH₃; —O—C(O)—CH₃ or —O—C(O)—C₂H₅; radicals of the formulae

—NH—SO₂CH₃ or —NH—SO₂C₆H₅, and R⁴ represents straight-chain or branched(C₁-C₄)-alkyl which is optionally mono- or polysubstituted by hydroxyl;amino; —C(O)—OCH₃; —C(O)—NH₂, —C(O)—HNCH₃, —C(O)—HNC₂H₅, or—C(O)—HNC₆H₅; —NHC(O)NH₂, —NHC(O)NHCH₃, —NHC(O)NHC₂H₅, —NHC(O)OCH₃ or—NHC(O)OC₂H₅; —SO₂—NH₂; —NH—SO₂—CH₃ or —NH—SO₂—C₂H₅; —OCH₃; phenyl,which may be substituted by nitro, cyano, fluorine, methoxy,difluoromethoxy, methoxycarbonyl or p-tolylsulfonylmethyl; pyridyl,furyl, imidazolyl, benzimidazolyl or thiazolyl, which may in each casebe mono- or disubstituted by identical or different substituents fromthe group consisting of methyl, nitro and chlorine; oxadiazolyl whichmay be substituted by phenyl or methoxyphenyl; or a radical of theformula

R⁴ represents allyl or 3,3-dimethylallyl, or a tautomer, salt, hydrate,or alkoxide thereof, except for the following compounds of the formula(I), in which the radicals R¹, R², R³ and R⁴ as defined below: R¹=R²=H;R³=para-OH; R⁴=—CH₂-Z where Z=H, C₆H₅, C(O)—OCH₃; R¹=R²=H;R³=para-O—C(O)—CH₃; R⁴=—CH₂-Z where Z=H; R¹=R²=R³=H; R⁴=—CH₂-Z whereZ=CH₃; R¹=R²=H; R³=meta-fluoro; R⁴=—CH₂-Z where Z=C(O)—NH₂; R¹=R²=H;R³=para-chloro; R⁴=—CH₂-Z where Z=CH₃; R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Zwhere Z=CH₃; R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.
 5. Thecompound of the formula (I) as claimed in any of claims 1 to 3, whereinR¹, R², R³ are identical or different and independently of one anotherare selected from the group consisting of the following substituents:hydrogen; hydroxyl; methyl; methoxy; radicals of the formulae—O—CH₂—CH₂—OH, —O—CH₂—COOH or —O—CH₂—CH═CH₂; fluorine or chlorine;nitro; cyano; —C(O)OH or —C(O)OCH₃; —C(O)NH₂; —NH₂; —NH—C(O)CH₃;—O—C(O)—CH₃ or —O—C(O)—C₂H₅; radicals of the formulae

—NH—SO₂CH₃ or —NH—SO₂C₆H₅, and R⁴ represents straight-chain or branched(C₁-C₄)-alkyl which is optionally mono- or polysubstituted by hydroxyl;amino; —C(O)—OCH₃; —C(O)—NH₂, —C(O)—HNCH₃, —C(O)—HNC₂H₅, or—C(O)—HNC₆H₅; —NHC(O)NH₂, —NHC(O)NHCH₃, —NHC(O)NHC₂H₅, —NHC(O)OCH₃ or—NHC(O)OC₂H₅; —SO₂—NH₂; —NH—SO₂—CH₃ or —NH—SO₂—C₂H₅; —OCH₃; phenyl;ortho-nitrophenyl; or a radical of the formula

R⁴ represents allyl, or a tautomer, salt, hydrate, or alkoxide thereof,except for the following compounds of the formula (I), in which theradicals R¹, R², R³ and R⁴ are as defined below: R¹=R²=H; R³=para-OH;R⁴=—CH₂-Z where Z=H, C₆H₅, C(O)—OCH₃; R¹=R²=H; R³=para-O—C(O)—CH₃;R⁴=—CH₂-Z where Z=H; R¹=R²=R³=H; R⁴=—CH₂-Z where Z=CH₃; R¹=R²=H;R³=meta-fluoro; R⁴=—CH₂-Z where Z=C(O)—NH₂; R¹=R²=H; R³=para-chloro;R⁴=—CH₂-Z where Z=CH₃; R¹=R²=H; R³=para-OCH₃; R⁴=—CH₂-Z where Z=CH₃;R¹=R²=H; R³=meta-NO₂; R⁴=—CH₂-Z where Z=CH₃.
 6. A process for preparingthe compounds of the formula (I) as defined in claim 1, wherein: acompound of the formula (II)

in which the radicals R¹, R² and R³ are as defined above in claim 1, isreacted with a compound of the formula (III)R⁴—X  (III), in which R⁴ is as defined above in claim 1 and X representsa nucleofugic group, in an inert solvent, if appropriate in the presenceof a base.
 7. A process for preparing the compounds of the formula (I)as defined in claim 1 in the case that in the formula (I) the radical R⁴has the meaning of alkyl, substituted by the radicals —NR⁶—C(O)—R⁸,—NR⁶—C(O)—NR⁶R⁷, —NR⁶—SO₂—R⁸ where the radicals R⁶, R⁷ and R⁸ are asdefined above in claim 1, wherein: initially the compound of the aboveformula (II) as defined in claim 6 is reacted with 2-bromoethylamine togive the compound of the formula (IV)

which is then reacted with a compound of the formulaR⁹—Y  (V), in which R⁹ has the meaning —C(O)—R⁸, —C(O)—O—R⁸,—C(O)—NR⁶R⁷, —SO₂—R⁸ where R⁸ is as defined above in claim 1, and Yrepresents a nucleofugic group, or R⁹ has the meaning R⁶ and Yrepresents the group O═C═N—, in an inert solvent, if appropriate in thepresence of a base.
 8. A method of treating or preventing a disordercomprising administering to a host in need thereof an effective amountof a compound of the formula (I)

wherein: R¹, R², R³ are identical or different and independently of oneanother are selected from the group consisting of the followingsubstituents: hydrogen; hydroxyl; optionally substituted (C₁-C₈)-alkyl;optionally substituted (C₆-C₁₀)-aryl; optionally substituted(C₁-C₈)-alkoxy; —O—(CH₂)_(n)—CH═CH₂ where n=0, 1 or 2; halogen; nitro;cyano; —C(O)—R⁵; —C(O)—NR⁶R⁷; —NR⁶R⁷; —NR⁶—C(O)—R⁸; —O—C(O)—R⁸;—SO₂—NR⁶R⁷; and —NR⁶—SO₂R⁸, where: R⁵ denotes: hydrogen; hydroxyl;optionally substituted (C₁-C₈)-alkyl; optionally substituted(C₃-C₇)-cycloalkyl; optionally substituted (C₁-C₈)-alkoxy; optionallysubstituted (C₆-C₁₀)-aryl; optionally substituted (C₆-C₁₀)-aryloxy; or—O—(CH₂)_(n)—[(C₆-C₁₀)-aryl] where n=1, 2 or 3, where the (C₆-C₁₀)-arylgroup may be fused via two adjacent ring atoms to optionally substituted(C₄-C₇)-cycloalkyl, or R⁵ represents a 5- to 7-membered saturated orunsaturated heterocycle which may be mono- or polysubstituted by an oxogroup (═O); halogen; optionally substituted (C₁-C₈)-alkyl; nitro; cyano;hydroxyl; optionally substituted (C₆-C₁₀)-aryl; or by (C₁-C₈)-alkoxy, orR⁵ represents optionally substituted 5- to 6-membered heteroaryl havingup to 3 heteroatoms from the group consisting of N, O and S, where theheterocycle and the heteroaryl ring may each optionally be fused via twoadjacent ring atoms to optionally substituted (C₆-C₁₀)-aryl oroptionally substituted (C₄-C₇)-cycloalkyl, and R⁶ and R⁷ are identicalor different and represent hydrogen; optionally substituted(C₁-C₈)-alkyl; optionally substituted (C₆-C₁₀)-aryl; or representoptionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S or R⁶ and R⁷together with the nitrogen atom to which they are optionally attachedform a 5- to 7-membered saturated or unsaturated heterocycle having upto 3 heteroatoms from the group consisting of N, O and S, which mayoptionally be mono- or polysubstituted by identical or differentsubstituents from the group consisting of an oxo group (═O); halogen;(C₁-C₈)-alkyl; nitro; cyano; hydroxyl; (C₆-C₁₀)-aryl; and(C₁-C₈)-alkoxy, and R⁸ represents hydroxyl; NR⁶R⁷ where R⁶ and R⁷ are asdefined above; optionally substituted (C₁-C₈)-alkyl; (C₁-C₈)-alkoxy;optionally substituted (C₆-C₁₀)-aryl; (C₆-C₁₀)-aryloxy; or—O—(CH₂)_(n)—[(C₆-C₁₀)-aryl] where n=1, 2 or 3, and R⁴ representsstraight-chain or branched (C₁-C₈)-alkyl or (C₂-C₈)-alkenyl which areoptionally mono- or polysubstituted by hydroxyl; halogen; cyano;—C(O)—R⁵ where R⁵ is as defined above; —C(O)—NR⁶R⁷ where R⁶ and R⁷ areas defined above; —NR⁶R⁷ where R⁶ and R⁷ are as defined above;—NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above; —SO₂—NR⁶R⁷ where R⁶and R⁷ are as defined above; —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are as definedabove; —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is as definedabove; (C₁-C₈)-alkoxy; optionally substituted (C₆-C₁₀)-aryloxy;optionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S; optionallysubstituted (C₆-C₁₀)-aryl; or by a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the groupconsisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); halogen; (C₁-C₈)-alkyl; nitro; cyano;hydroxyl; (C₆-C₁₀)-aryl; or by (C₁-C₈)-alkoxy, where the heterocycle andthe heteroaryl ring may each optionally be fused via two adjacent ringatoms to optionally substituted (C₆-C₁₀)-aryl, or R⁴ represents a 5- to7-membered saturated or unsaturated heterocycle having up to 3heteroatoms from the group consisting of N, O and S, which mayoptionally be mono- or polysubstituted by identical or differentsubstituents from the group consisting of an oxo group (═O); halogen;(C₁-C₈)-alkyl; nitro; cyano; hydroxyl; (C₆-C₁₀)-aryl; or by(C₁-C₈)-alkoxy, and which may optionally be fused via two adjacent ringatoms to optionally substituted (C₆-C₁₀)-aryl or optionally substituted(C₄-C₇)-cycloalkyl, or a tautomer, salt, hydrate, or alkoxide thereof.9. A method of treating or preventing a disorder comprisingadministering to a host in need thereof an effective amount of thecompound of the formula (I) as claimed in claim 8, wherein: R¹, R², R³are identical or different and independently of one another are selectedfrom the group consisting of the following substituents: hydrogen;hydroxyl; optionally substituted (C₁-C₆)-alkyl; optionally substitutedphenyl or naphthyl; optionally substituted (C₁-C₆)-alkoxy;—O—(CH₂)_(n)—CH═CH₂ where n=1 or 2; fluorine, chlorine, bromine; nitro;cyano; —C(O)—R⁵; —C(O)—NR⁶R⁷; —NR⁶R⁷; —NR⁶—C(O)—R⁸; —O—C(O)—R⁸;—SO₂—NR⁶R⁷; and —NR⁶—SO₂R⁸, where: R⁵ denotes: hydrogen; hydroxyl;optionally substituted (C₁-C₆)-alkyl; optionally substituted(C₃-C₇)-cycloalkyl; optionally substituted (C₁-C₆)-alkoxy; optionallysubstituted phenyl or naphthyl; optionally substituted phenyloxy ornaphthyloxy; or —O—(CH₂)_(n)-phenyl where n=1, 2 or 3, where the phenylor naphthyl group may be fused via two adjacent ring atoms to optionallysubstituted (C₄-C₇)-cycloalkyl, or R⁵ represents a 5- to 7-memberedsaturated or unsaturated heterocycle which may be mono- orpolysubstituted by an oxo group (═O); fluorine, chlorine, bromine;optionally substituted (C₁-C₆)-alkyl; nitro; cyano; hydroxyl; optionallysubstituted phenyl or naphthyl; or by (C₁-C₆)-alkoxy, or R⁵ representsoptionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S, where theheterocycle and the heteroaryl ring may each optionally be fused via twoadjacent ring atoms to optionally substituted phenyl or naphthyl oroptionally substituted (C₄-C₇)-cycloalkyl, and R⁶ and R⁷ are identicalor different and represent hydrogen; optionally substituted(C₁-C₆)-alkyl; optionally substituted phenyl or naphthyl; or representoptionally substituted 5- to 6-membered heteroaryl having up to 3heteroatoms from the group consisting of N, O and S or R⁶ and R⁷together with the nitrogen atom to which they are optionally attachedform a 5- to 7-membered saturated or unsaturated heterocycle having upto 3 heteroatoms from the group consisting of N, O and S, which mayoptionally be mono- or polysubstituted by identical or differentsubstituents from the group consisting of an oxo group (═O); fluorine,chlorine, bromine; (C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl ornaphthyl; and (C₁-C₆)-alkoxy, and R⁸ represents NR⁶R⁷ where R⁶ and R⁷are as defined above; optionally substituted (C₁-C₆)-alkyl;(C₁-C₆)-alkoxy; optionally substituted phenyl or naphthyl; phenyloxy ornaphthyloxy; or —O—(CH₂)_(n)-phenyl where n=1, 2 or 3, and R⁴ representsstraight-chain or branched (C₁-C₆)-alkyl or (C₂-C₆)-alkenyl which areoptionally mono- or polysubstituted by hydroxyl; fluoro, chloro,bromine; cyano; —C(O)—R⁵ where R⁵ is as defined above; —C(O)—NR⁶R⁷ whereR⁶ and R⁷ are as defined above; —NR⁶R⁷ where R⁶ and R⁷ are as definedabove; —NR⁶C(O)—R⁸ where R⁶ and R⁸ are as defined above; —SO₂—NR⁶R⁷where R⁶ and R⁷ are as defined above; —NR⁶—SO₂—R⁸ where R⁶ and R⁸ are asdefined above; —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 and R⁸ is asdefined above; (C₁-C₆)-alkoxy; optionally substituted phenyloxy ornaphthyloxy; optionally substituted 5- to 6-membered heteroaryl havingup to 3 heteroatoms from the group consisting of N, O and S; optionallysubstituted phenyl or naphthyl; or by a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the groupconsisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); fluorine, chlorine, bromine;(C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl or naphthyl; or by(C₁-C₆)-alkoxy, where the heterocycle and the heteroaryl ring may eachoptionally be fused via two adjacent ring atoms to optionallysubstituted phenyl or naphthyl, or R⁴ represents a 5- to 7-memberedsaturated or unsaturated heterocycle having up to 3 heteroatoms from thegroup consisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); fluorine, chlorine, bromine;(C₁-C₆)-alkyl; nitro; cyano; hydroxyl; phenyl or naphthyl; or by(C₁-C₆)-alkoxy and which may optionally be fused via two adjacent ringatoms to optionally substituted phenyl or naphthyl or optionallysubstituted (C₄-C₇)-cycloalkyl, or a tautomer, salt, hydrate, oralkoxide thereof.
 10. A method of treating or preventing a disordercomprising administering to a host in need thereof an effective amountof the compound of the formula (I) as claimed in claim 9, wherein: R¹,R², R³ are identical or different and independently of one another areselected from the group consisting of the following substituents:hydrogen; hydroxyl; optionally substituted (C₁-C₄)-alkyl; optionallysubstituted phenyl; optionally substituted (C₁-C₄)-alkoxy;—O—(CH₂)_(n)—CH═CH₂ where n=1; fluorine, chlorine; nitro; cyano;—C(O)—R⁵; —C(O)—NR⁶R⁷; —NR⁶R⁷; —NR⁶—C(O)—R⁸; —O—C(O)—R⁸; —SO₂—NR⁶R⁷; and—NR⁶—SO₂R⁸, where: R⁵ denotes: hydrogen; hydroxyl; optionallysubstituted (C₁-C₄)-alkyl; optionally substituted (C₃-C₇)-cycloalkyl;optionally substituted (C₁-C₄)-alkoxy; optionally substituted phenyl;optionally substituted phenyloxy; or —O—(CH₂)_(n)-phenyl where n=1,where the phenyl group may be fused via two adjacent ring atoms tooptionally substituted (C₅-C₆)-cycloalkyl, or R⁵ represents a 5- to7-membered saturated or unsaturatedheterocycle which may be mono- orpolysubstituted by an oxo group (═O); fluorine, chlorine; optionallysubstituted (C₁-C₄)-alkyl; nitro; cyano; hydroxyl; optionallysubstituted phenyl; or by (C₁-C₄)-alkoxy, or R⁵ represents optionallysubstituted 5- to 6-membered heteroaryl having up to 3 heteroatoms fromthe group consisting of N, O and S, selected from the group consistingof furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,triazolyl, pyridyl, pyrimidyl and pyridazinyl, where the heterocycle andthe heteroaryl ring may each optionally be fused via two adjacent ringatoms to optionally substituted phenyl or optionally substituted(C₅-C₆)-cycloalkyl, and R⁶ and R⁷ are identical or different andrepresent hydrogen; optionally substituted (C₁-C₄)-alkyl; optionallysubstituted phenyl; or represent optionally substituted 5- to 6-memberedheteroaryl having up to 3 heteroatoms from the group consisting of N, Oand S selected from the group consisting of furanyl, pyrrolyl, thienyl,thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl andpyridazinyl, or R⁶ and R⁷ together with the nitrogen atom to which theyare optionally attached form a 5- to 7-membered saturated or unsaturatedheterocycle having up to 3 heteroatoms from the group consisting of N, Oand S, which may optionally be mono- or polysubstituted by identical ordifferent substituents from the group consisting of an oxo group (═O);fluorine, chlorine; (C₁-C₄)-alkyl; nitro; cyano; hydroxyl; phenyl; and(C₁-C₄)-alkoxy, and R⁸ represents NR⁶R⁷ where R⁶ and R⁷ are as definedabove; optionally substituted (C₁-C₄)-alkyl; (C₁-C₄)-alkoxy; optionallysubstituted phenyl; phenyloxy; or —O—(CH₂)_(n)-phenyl where n=1, and R⁴represents straight-chain or branched (C₁-C₄)-alkyl or (C₂-C₄)-alkenylwhich are optionally mono- or polysubstituted by hydroxyl; fluorine,chlorine; cyano; —C(O)—R⁵ where R⁵ is as defined above; —C(O)—NR⁶R⁷where R⁶ and R⁷ are as defined above; —NR⁶R⁷ where R⁶ and R⁷ are asdefined above; —NR⁶—C(O)—R⁸ where R⁶ and R⁸ are as defined above;—SO₂—NR⁶R⁷ where R⁶ and R⁷ are as defined above; —NR⁶—SO₂—R⁸ where R⁶and R⁸ are as defined above; —C(O)—(CH₂)_(n)—C(O)—R⁸ where n=0 to 2 andR⁸ is as defined above; (C₁-C₄)-alkoxy; optionally substitutedphenyloxy; optionally substituted 5- to 6-membered heteroaryl having upto 3 heteroatoms from the group consisting of N, O and S selected fromthe group consisting of furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl; optionallysubstituted phenyl; or by a 5- to 7-membered saturated or unsaturatedheterocycle having up to 3 heteroatoms from the group consisting of N, Oand S, which may optionally be mono- or polysubstituted by identical ordifferent substituents from the group consisting of an oxo group (═O);fluorine, chlorine; (C₁-C₄)-alkyl; nitro; cyano; hydroxyl; phenyl; or by(C₁-C₄)-alkoxy, where the heterocycle and the heteroaryl ring may eachoptionally be fused via two adjacent rings atoms to optionallysubstituted phenyl, or R⁴ represents a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the groupconsisting of N, O and S, which may optionally be mono- orpolysubstituted by identical or different substituents from the groupconsisting of an oxo group (═O); fluorine, chlorine; (C₁-C₄)-alkyl;nitro; cyano; hydroxyl; phenyl; or by (C₁-C₄)-alkoxy and which mayoptionally be fused via two adjacent ring atoms to optionallysubstituted phenyl or optionally substituted (C₅-C₆)-cycloalkyl, or atautomer, salt, hydrate, or alkoxide thereof.
 11. A method of treatingor preventing a disorder comprising administering to a host in needthereof an effective amount of the compound of the formula (I) asclaimed in claim 10, wherein: R¹, R², R³ are identical or different andindependently of one another are selected from the group consisting ofthe following substituents: hydrogen; hydroxyl; methyl; trifluoromethyl;methoxy; radicals of the formulae —O—CH₂—CH₂—OH, —O—CH₂—COOH or—O—CH₂—CH═CH₂; fluorine, chlorine or bromine; nitro; cyano; —C(O)OH or—C(O)OCH₃; —C(O)NH₂; —NH₂; —NH—C(O)—CH₃; —O—C(O)—CH₃ or —O—C(O)—C₂H₅;radicals of the formulae

—NH—SO₂CH₃ or —NH—SO₂C₆H₅, and R⁴ represents straight-chain or branched(C₁-C₄)-alkyl which is optionally mono- or polysubstituted by hydroxyl;amino; —C(O)—OCH₃; —C(O)—NH₂, —C(O)—HNCH₃, —C(O)—HNC₂H₅, or—C(O)—HNC₆H₅; —NHC(O)NH₂, —NHC(O)NHCH₃, —NHC(O)NHC₂H₅, —NHC(O)OCH₃ or—NHC(O)OC₂H₅; —SO₂—NH₂; —NH—SO₂—CH₃ or —NH—SO₂—C₂H₅; —OCH₃; phenyl,which may be substituted by nitro, cyano, fluorine, methoxy,difluoromethoxy, methoxycarbonyl or p-tolylsulfonylmethyl; pyridyl,furyl, imidazolyl, benzimidazolyl or thiazolyl, which may in each casebe mono- or disubstituted by identical or different substituents fromthe group consisting of methyl, nitro and chlorine; oxadiazolyl whichmay be substituted by phenyl or methoxyphenyl; or a radical of theformula

R⁴ represents allyl or 3,3-dimethylallyl, or a tautomer, salt, hydrate,or alkoxide thereof.
 12. A method of treating or preventing a disordercomprising administering to a host in need thereof an effective amountof the compound of the formula (I) as claimed in to claim 11, wherein:R¹, R², R³ are identical or different and independently of one anotherare selected from the group consisting of the following substituents:hydrogen; hydroxyl; methyl; methoxy; radicals of the formulae—O—CH₂—CH₂—OH, —O—CH₂—COOH or —O—CH₂—CH═CH₂; fluorine or chlorine;nitro; cyano; —C(O)OH or —C(O)OCH₃; —C(O)NH₂; —NH₂; —NH—C(O)CH₃;—O—C(O)—CH₃ or —O—C(O)—C₂H₅; radicals of the formulae

—NH—SO₂CH₃ or —NH—SO₂C₆H₅, and represents straight-chain or branched(C₁-C₄)-alkyl which is optionally mono- or polysubstituted by hydroxyl;amino; —C(O)—OCH₃; —C(O)—NH₂, —C(O)—HNCH₃, —C(O)—HNC₂H₅, or—C(O)—HNC₆H₅; —NHC(O)NH₂, —NHC(O)NHCH₃, —NHC(O)NHC₂H₅, —NHC(O)OCH₃ or—NHC(O)OC₂H₅; —SO₂—NH₂; —NH—SO₂—CH₃ or —NH—SO₂—C₂H₅; —OCH₃; phenyl;ortho-nitrophenyl; or a radical of the formula

R⁴ represents allyl, or a tautomer, salt, hydrate, or alkoxide thereof.13. A pharmaceutical composition, comprising at least one compound ofthe formula (I) as defined in claim 1, plus at least onepharmaceutically acceptable carrier or excipient.
 14. A pharmaceuticalcomposition, comprising at least one selective adenosine receptorligand, selected from the group consisting of Adenosine A1 receptorligands, Adenosine A2a receptor ligands and Adenosine A2b receptorligands, plus at least one pharmaceutically acceptable carrier orexcipient.
 15. (canceled)
 16. A method for the prophylaxis and/ortreatment of a disorder selected from the group consisting ofcardiovascular disorders; urogenital disorders; respiratory disorders;inflammatory and neuroinflammatory disorders; diabetes,neurodegenerative disorders; pain; cancer; and also hepatic fibrosis andcirrhosis of the liver, comprising administering to a host in needthereof an effective amount of a compound of formula (I) as defined inclaim
 1. 17. A method for the prophylaxis and/or treatment of a disorderselected from the group consisting of cardiovascular disorders;urogenital disorders; respiratory disorders; inflammatory andneuroinflammatory disorders; diabetes, neurodegenerative disorders;pain; cancer; hepatic fibrosis and cirrhosis of the liver, comprisingadministering to a host in need thereof an effective amount of aselective adenosine receptor ligand selected from the group consistingof adenosine A1 receptor ligands, adenosine A2a receptor ligands, andadenosine A2b receptor ligands.
 18. The process of claim 6 wherein thenucleofugic group X in formula (III) is halogen, mesylate, tosylate,triflate or 1-imidazolyl.
 19. The process of claim 18 wherein saidhalogen is chlorine, bromine or iodine.
 20. The process of claim 7wherein the nucleofugic group Y in formula (V) represents halogen,mesylate, tosylate, triflate or 1-imidazolyl.
 21. The process of claim20 wherein said halogen is chlorine, bromine or iodine,
 22. The methodof claim 16 wherein the disorder is diabetes mellitus.
 23. The method ofclaim 17 wherein the disorder is diabetes mellitus.